Methods and articles for delivering viable cells into solid tissue

ABSTRACT

Embodiments provide swallowable devices, preparations and methods for delivering viable cells (VC) into the GI tract including GI wall tissue or other tissue site. Particular embodiments provide a swallowable device such as a capsule for delivering VC into an intestinal wall or other site. The VC can be contained within a tissue-penetrating shell disposed in the capsule that protects the VC as they pass through the GI tract until they are inserted into GI tract tissue or other location. The shell desirably has shape, size and material consistency to be contained in a swallowable capsule, delivered from the capsule into solid tissue by the application of force on the shell and biodegrade within the solid tissue to release the VC into the tissue. Within the shell or other structure the VC can be maintained in a viability-sustaining gel that preserves the viability of the VC for selected time periods.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.15/455,080, filed Mar. 9, 2017, now U.S. Pat. No. 10,220,003, whichclaims the benefit of priority to Provisional U.S. patent applicationSer. No. 62/305,878, filed Mar. 9, 2016; the entire contents of whichare incorporated herein by reference.

This application is also related to co-filed U.S. patent applicationSer. No. 15/455,075, the full disclosure of which is incorporated hereinfor all purposes. This disclosure of the application incorporatesdisclosure from U.S. patent application Ser. No. 13/837,025, now U.S.Pat. No. 8,734,429, filed Mar. 15, 2013, the entire contents of whichare hereby incorporated by reference herein for all purposes.

BACKGROUND OF THE INVENTION 1. Field of the Invention

Embodiments of the invention relate to swallowable viable cells deliverydevices. More specifically, embodiments of the invention relate toswallowable delivery devices for delivering viable cells to the smallintestine and other solid tissues.

While there has been an increasing development of new viable cells inrecent years for the treatment of a variety of diseases, many includingproteins, antibodies and peptides have limited application because theycannot be given orally. This is due to a number of reasons including:poor oral toleration with complications including gastric irritation andbleeding; breakdown/degradation of the viable cells compounds in thestomach; and poor, slow or erratic absorption of the viable cells.Conventional alternative viable cells delivery methods such asintravenous and intramuscular delivery have a number of drawbacksincluding pain and risk of infection from a needle stick, requirementsfor the use of sterile technique and the requirement and associatedrisks of maintaining an IV line in a patient for an extended period oftime. While other viable cells delivery approaches have been employedsuch as implantable viable cells delivery pumps, these approachesrequire the semi-permanent implantation of a device and can still havemany of the limitations of IV delivery. Thus, there is a need for animproved method for delivery of viable cells and other therapeuticagents.

U.S. Pat. Nos. 8,721,620; 8,759,284; and 8,734,429, all commonlyassigned with the present patent application, describe swallowabledevices which are optimized for the delivery of proteins and otherlabile viable cells to a patient's intestines. While very effective fordelivering viable cells formulations, these devices are not optimizedfor delivering living cells to a patient. The delivery of living orviable cells, such as stem cells, cells which secrete therapeuticallybeneficial agents, and the like, to a patient promises to be of enormousclinical benefit, but is hindered by a shortage of effective deliveryapparatus, materials and protocols.

For these reasons, it would be desirable to provide improved andalternative apparatus, materials and protocols for the delivery ofviable cells to human and animal patients. At least some of theseobjectives will be met by the inventions described and claimed herein.

2. Description of the Background Art

U.S. Pat. Nos. 8,721,620; 8,759,284; and 8,734,429 have been describedabove. See also US2013/0095081 and US 2010/0215715.

SUMMARY OF THE INVENTION

Embodiments of the present invention provide articles, methods, devices,and systems for delivering viable cells into solid tissue into thegastro intestinal tract and organs of digestion. The viable cells can bedelivered for one or both of therapeutic and diagnostic purposes. Theviable cells will typically be delivered to human patients but couldalso be delivered to other mammalian animals for veterinary purposes.The viable cells may include a variety of mammalian cells types such aspancreatic enteroendocrine cells, for example beta cells; Gastricenteroendocrine cells such as G-cells; or Intestinal enteroendocrinecells such as L-cells K-cells, I-cells, N-cells and S-cells. They mayalso include various mucosal cells, including for example,gastro-intestinal mucosal cells Viable cells being delivered willtypically produce therapeutically beneficial agents, such as pancreaticbeta cells which produce insulin; immune cells which produce proteins ofthe immune system, incretin producing cells such as L-cells, K-cells,and a variety of stem cells such as mesenchymal stem cells,hematopoietic stem cells, and the like. The cells will typically bedelivered to the patient's intestinal tissue, usually via an oraldelivery route where the viable cells pass through the gastrointestinaltract before being delivered to the intestinal tissue. A particularadvantage of the present invention is that viability of the cells can bemaintained as the cells pass through the gastrointestinal tract prior todelivery into the intestinal tissue, the delivery of which can take manyhours during which the viability of the cells is at risk.

In a first aspect, the present invention provides articles fordelivering viable cells into solid tissue. The articles include a shellconfigured for self-penetration into the solid tissue, typically havinga sharpened, pointed, conical, or other conventional tissue-penetratingtip. In other embodiments, the self-penetrating tip may include anelectrosurgical element (e.g. and RF energy powered element) to enhancepenetration into tissue. A mass of viable therapeutic cells ismaintained within an interior of the shell under conditions whichpromote viability. In particular embodiments, cells will usually bemaintained in preparation including a viability-sustaining gel, such asan alginate gel, a protein gel, a glycosaminoglycan gel, a carbohydrategel, or other conventional gel or medium known for maintaining mammaliancell viability. In particular embodiments the gel can be saturated orpartially saturated with oxygen to provide further viability sustainingqualities to the gel. This may be done before or after addition of thecells to the gel. Once penetrated or otherwise placed into tissue, thearticle is configured to degrade (also referred to as biodegrade) intissue to release the mass of viable cells into tissue.

In certain embodiments, the shell of the article will be configured tobiodegrade over a time period of at least 12 hours, i.e. the shell willnot degrade during the initial 12 hours it is within the patientgastrointestinal tract or elsewhere. Often, the time period fordegradation is in the range from 4 hours to one year, typically beingfrom ½ days to 5 days with specific embodiments of 1, 2, 3, 4 days.Often, it will be an objective of the present invention to maintain theshell only for so long as necessary to protect the cells from passagethrough the gastrointestinal tract and to release the shells fromcontainment as quickly as possible after implantation into theintestinal wall or other location.

A variety of specific materials may be used for the biodegradableshells, including biodegradable metals, such as magnesium, iron, andzinc. Biodegradable polymers will also be useful, including, forexample, poly lactic acid (PLA), poly lactic-co-glycolic acid (PLGA) andvarious sugars such as maltose, sucrose and the like. Further accordingto one or more embodiments the shell may comprise multiple layers of thesame or different materials with the layers configured to degrade atdifferent rates (e.g. hours vs days). In use such embodiments allow fora rapid release of cells followed for example for the rapid generationof a particular therapeutic substance such as insulin, followed by alonger term release to allow for the longer term release. Forembodiments of the article configured for the treatment of diabetes orother glucose regulation disorder this allows for a short term andlonger term treatment of the disease or condition. The variation in thedegradation rates can be controlled by selection of one or more of thethickness, surface area, material and material properties of the shell.

In certain embodiments, the shell of the delivery article may havefenestrations, e.g., holes, apertures, or other small passages formedthere through. The fenestrations will be configured to allow passage offluids and small molecules into and out of an interior of the shell, butto contain the cells and the gel within the interior of the shell. Invarious embodiments the fenestrations can have a diameter a selecteddiameter matched to a selected percentage (e.g., 1, 5, 10, 25, 50% etc.)to the major diameter of the particular cell or cells contained withinthe article. The fenestrations will typically have a width in the rangefrom about 0.1 to 15 μm more preferably about 0.5 to 5 μm and/or an areain the range from 0.03 to 700 μm² more preferably about 0.8 to 80 μm².When the shell comprises fenestrations, it may be formed from anon-biodegradable material since many cells can maintain viabilitythrough fluid and substance exchange with the implanted tissue and canrelease therapeutically useful cell products to the tissue through thesame fenestrations. Usually, however, even with fenestrations, it willbe preferable to form the wall from the biodegradable material. In analternative or additional embodiment the fenestrations may be configuredto produce a distinct acoustical signature or pattern when pinged by anexternal acoustical transceiver such as an ultrasound transceiver orother piezo electric based acoustical transceiver. Further as thefenestrations break down due to bioerosion of the article the acousticalsignature of shell in response to the ping changes such the degree ofbio-erosion of the shell can be discerned. In particular embodiments thefenestrations can be configured to produce distinct acoustical patternswhen there is no bio-erosion, and when there is 25, 50 and 75%bio-erosion. In this way, the fenestrations provide actionableinformation for the user to know when the article has degradedsufficiently to release the cells to the selected tissue site. Thespecific acoustical signatures can be produced by the size and spacingof the fenestrations. In alternative or additional embodiments forproviding information on the state of degradation of the articles, thearticles can include acoustical markers or indicia configured to providespecific acoustical signatures of the percent degradation of thearticle.

In a second aspect, the present invention provides methods fordelivering viable cells into solid tissues such as the tissue in thewalls of the intestinal tract such as the small intestine and/or thedigestive organs such as the pancreas. The methods compriseadministering an article to a patient, such as a tissue penetratingmember, where the article contains a selected mass or volume oftherapeutic cells in a viable state. Typically, the mass of cells willbe contained in preparation comprising the cells and a viabilitysustaining gel described herein. The article is then penetrated into thesolid tissue, and at least a portion of the article biodegrades torelease the cells within the tissue in a viable state. The cells arethen available to produce therapeutically useful agents and substanceswhich can be released directly into the tissue in which the cells havebeen implanted. In certain embodiments of this method, administeringcomprises the patient swallowing the article, which may be contained inswallowable capsule described herein, where the article passes throughthe patient's gastrointestinal tract and into the patient's intestines.Once resident in the intestines, the article will be propelled into theintestinal wall by operative coupling with an expansion means such as anexpandable balloon that contains chemical reactants which produce a gasupon being mixed so to expand the balloon. Typically, this will be doneresponse to a pH change within the intestines, such as the higher pH inthe small intestine, where said pH change triggers the chemical reactionwhich results in propulsion of the article into the intestinal wall.Other means for generating a propulsive force so at to have the articlepenetrate and be inserted into the intestinal wall are alsocontemplated. For example, a propulsive force may be generated throughthe use of an electromagnetic force (from piezo electro material), ahydrostatic force or a spring force.

In a third aspect, the invention provides methods for delivering viablecells into solid tissues such as the tissue in the walls of theintestinal tract wherein the cells are put into a reversible suspendedstate of animation prior to being administered to the patient (includingprior to being put into the article) wherein they reanimate after beingdelivered to the patient so as to produce a therapeutic effect. Suchtherapeutic effects can include for example the cellular production ofone or more therapeutic compounds (e.g., insulin, integrins, etc.).Typically, this will be done by freezing or chilling the cells and/orthe gel containing them within the article prior to administering thearticle to the patient. Chilling may be done to a temperature in therange of 50 to 33° F. with a preferred range of 39 to 40° F. In analternative or variation, the cells and/or gel containing them may befrozen or chilled prior to being placed into the article. Freezing orchilling the articles and the cells therein prior to administration isparticularly useful as it can preserve the cells for extended periods oftime in a reversible state of suspended animation without the need tosupply nutrients and remove cellular products. Once articles areadministered to the patient, however, the cells will thaw and warmwithin a short time period to become reanimated and will resume cellularprocesses and may be at risk of degradation from the gastrointestinalenvironment. The shell of the article, as described above, will protectthe now metabolically active cells as they pass through a patient'sgastrointestinal tract where they would be exposed to the digestiveconditions of the stomach which, without protection, would damage orkill the cells. Once penetrated into the intestinal tract, the articlewill be implanted into the intestinal tissue, thus releasing the viablecells where they are now in an environment in which cell viability canbe maintained and they can generate the useful therapeutic substanceswhich they produce. Embodiments of these methods employ articles whichmay have the preferred characteristics and dimensions discussed above inconnection with articles of the present invention. Other methods ofsuspended reversible animation of the viable cells are also contemplatedbesides freezing and chilling. These may include for example, use ofcertain compounds in the gel and/or charging the gel with an inert gas(e.g., nitrogen) and lyophilizing of the cells (or other freeze dryingmethods) prior to administration.

As discussed above for embodiments where the cells are orally delivered,the frozen, chilled or otherwise suspended cells pass through thepatient's gastrointestinal tract and are protected from conditions ofthe gastrointestinal tract by a barrier provided by the article. Thebarrier remains intact while the article passes through gastrointestinaltract, but the barrier will erode over time within the intestinal tissueto release the cells and/or therapeutically beneficial cellular productsover time. In use, such methods allow for the long term storage of thecells allowing the patient to store the articles containing the cells athome and take them over an extended period of weeks to months. Inembodiments where the cells are frozen or chilled, the article itselfcan be configured to be frozen. In particular embodiments it can beconfigured to be frozen without undergoing cracking or other structuraldeformations which may compromise the barrier function of the article.Further the space in the article interior may be increased relative toarticles containing non frozen cells so as to account for any expansionof the gel or other medium containing the cells due to freezing so thatthe article as well the cells are not damaged during freezing.Alternatively, the article interior may be only partially filled toprovide for expansion of the gel during freezing. These specificmaterials and dimensions of the article's use in this second method arealso described in more detail with respect to the articles of thepresent invention.

In a fourth aspect, the invention provides a method whereby the patientcan take a regimen of swallowable articles containing viable cells overa period of days, weeks or months so as to achieve a desired therapeuticeffect. For example, the patient may take a regimen of articlescontaining various doses of L-cells or K-cells to reestablish incretinproduction in the small intestine over a period of time and in turnglucose regulation or G-cells to reestablish the production of gastrinin the stomach or small intestine over a period of time so as to improveone or more of acid production, mucosal architecture and celldifferentiation in the GI tract including the stomach, small and largeintestine. The regimen may include varying the doses over the period oftime including for example an initial dose followed by lower maintenancedoses. These specific materials and dimensions of the article's use inthis second method are also described in more detail with respect to thearticles of the present invention.

In a fifth aspect, the invention provides methods whereby the patienttakes swallowable articles containing viable cells to reseed selectedportions of the GI tract with cells such as hormone or other peptideproducing cells that produce a desired therapeutic effect. For example,L-cells or K-cells to produce incretin or G-cells to produce Gastrin. Inspecific embodiments, the cells can comprise various mucosal cells toreseed the mucosa of the stomach, pylorus and duodenum to treat one ormore of a gastric, pyloric or duodenal ulcer. Further the articles canbe configured to reseed specific portions of specific GI organs such asthe duodenum or jejunum of the small intestine and the pyloric region ofthe stomach. The articles can be configured to inject cells into thesesspecific regions by the use of pH sensitive coatings described hereinsuch as various EUDRAGIT coatings and others known in the art whichdegrade in response to specific pH's in specific location, such as moreacid pH in the stomach (1.5-3.5) and increasingly less acidic pH in thesmall intestine (5.5 in the duodenum and 6.5-6.8 in the jejunum).

Further details of these and other embodiments and aspects of theinvention are described more fully below, with reference to the attacheddrawing figures.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a lateral viewing showing an embodiment of a swallowableviable cells delivery device.

FIG. 1B is a lateral viewing showing an embodiment of a system includinga swallowable viable cells delivery device.

FIG. 1C is a lateral viewing showing an embodiment of a kit including aswallowable viable cells delivery device and a set of instructions foruse.

FIG. 1D is a lateral viewing showing an embodiment of a swallowableviable cells delivery device including a viable cells reservoir.

FIG. 1E is a lateral viewing illustrating use of an embodiment of aswallowable viable cells delivery device including transit of device inthe GI tract and operation of the device to deliver viable cells.

FIGS. 2A and 2B are lateral views illustrating an embodiment of acapsule for the swallowable viable cells delivery device including a capand a body coated with pH sensitive biodegradable coatings, FIG. 2Ashows the capsule in an unassembled state and FIG. 2B in an assembledstate.

FIGS. 3A and 3B illustrate embodiments of unfolded multi balloonassemblies containing a deployment balloon, an aligner balloon, adelivery balloon and assorted connecting tubes; FIG. 3A shows anembodiment of the assembly for a single dome configuration of thedeployment balloon; and FIG. 3B shows an embodiment of the assembly fordual dome configuration of the deployment balloon;

FIG. 3C is a perspective views illustrating embodiments of a nestedballoon configuration which can be used for one or more embodiments ofthe balloons described herein including the aligner balloon.

FIGS. 4A-4C are lateral views illustrating embodiments of a multicompartment deployment balloon; FIG. 4A shows the balloon in anon-inflated state with the separation valve closed; FIG. 4B shows theballoon with valve open and mixing of the chemical reactants; and FIG.4C shows the balloon in an inflated state.

FIGS. 5A-5G are lateral views illustrating a method for folding of themultiple balloon assembly, the folding configuration in each figureapplies to both single and dual dome configurations of the deploymentballoon, with the exception that FIG. 5C, pertains to a folding stepunique to dual dome configurations; and FIG. 5D, pertains to the finalfolding step unique to dual dome configurations; FIG. 5E, pertains to afolding step unique to single dome configurations; and FIGS. 5F and 5Gare orthogonal views pertaining to the final folding step unique tosingle dome configurations.

FIGS. 6A and 6B are orthogonal views illustrating embodiments of thefinal folded multi balloon assembly with the attached delivery assembly.

FIGS. 7A and 7B are orthogonal transparent views illustratingembodiments of the final folded multi balloon assembly inserted into thecapsule.

FIG. 8A is a cross-sectional view of an embodiment of a tissuepenetrating article constructed in accordance with the principles of thepresent invention.

FIG. 8B is a cross-sectional view of an alternative embodiment of atissue penetrating article constructed in accordance with the principlesof the present invention.

FIG. 8C is a cross-sectional view of a yet another alternativeembodiment of a tissue penetrating article constructed in accordancewith the principles of the present invention which includes a moisturebarrier on an inner surface of the article.

FIG. 8D is a cross-sectional view of a yet another alternativeembodiment of a tissue penetrating article constructed in accordancewith the principles of the present invention which includes a shockabsorbing structure in an interior of the article and/or a shockabsorbing gel configured to reduce forces imparted onto the viablecells.

FIG. 9 provides assorted views of the components and steps used toassemble an embodiment of the delivery assembly.

FIGS. 10A-10I provide assorted views illustrating a method of operationof swallowable device to deliver viable therapeutic cells to theintestinal wall.

FIG. 11A shows an embodiment of a swallowable viable cells deliverydevice including a capsule having bio-degradable seams positioned toproduce controlled degradation of the capsule in the GI tract.

FIG. 11B shows the embodiment of FIG. 11A after having been degraded inthe GI tract into smaller pieces.

FIGS. 12A-B show an embodiment of a capsule having a piston-cylinderassembly.

FIG. 12C shows an embodiment of a delivery mechanism having an array ofpiston-cylinder assemblies.

FIG. 12D shows an embodiment of a capsule having a piston-cylinderassembly and a deflation valve.

FIG. 13A shows an embodiment of a delivery mechanism having deliveryballoon and a delivery compartment.

FIG. 13B depicts a balloon inflation pressure curve including a puncturepressure at which the puncture needles puncture the balloon.

FIG. 14 shows an embodiment of a capsule having biodegradable seamsincluding pores and/or perforations to accelerate biodegradation of thecapsule.

FIGS. 15A-15B show an embodiment of a capsule having tearable seamsarranged in a radial or lateral pattern for tearing of the capsule byinflation of the expandable balloon; FIG. 15A shows the capsule prior toinflation and FIG. 15B shows the capsule broken into pieces by theinflation of the balloon.

FIG. 16 shows an embodiment of a balloon tearable capsule fabricatedfrom separate portions joined by seams, which can be torn by inflationof the expandable balloon.

DETAILED DESCRIPTION OF THE INVENTION

Embodiments of the invention provide devices, preparations, systems andmethods for delivering viable cells in to various locations in the body,in particular to the intestinal wall tissue. In many embodiments thecells will be delivered by a swallowable device configured to maintainviability of the cells while they pass through the gastrointestinaltract and to a selected site within intestinal tract or other location.As used herein, “GI tract” refers to the esophagus, stomach, smallintestine, large intestine and anus, while “Intestinal tract” refers tothe small and large intestine. Various embodiments of the invention canbe configured and arranged for delivery of viable cells into theintestinal tract as well as the entire GI tract. Also in manyembodiments the delivered cells will comprise therapeutic cells and willsometimes be referred to as such. However embodiments of the inventionare not limited to therapeutic cells only. In particular it should beunderstood that the delivered cells may also comprise cells used fordiagnostic purposes. Also in various embodiments, the term preparation100 is used to described a preparation comprising viable cells 101including viable therapeutic cells. Preparation 100 will sometimes bereferred to as a “viable cell preparation”, “cell preparation” or just“preparation” 100 with all three being interchangeable. Further inaddition to viable cells 101, in various embodiments, preparation 100may comprise one or more drugs or other therapeutic agents, diagnosticsagents, and various excipients described herein and known in the art. Inparticular embodiments, preparation 100 also includes a viabilitypreserving gel 49 as is described herein.

Referring now to FIGS. 1-9, an embodiment of a device 10 for thedelivery of a preparation 100 comprising viable cells 101 to a deliverysite DS in the gastro-intestinal (GI) tract, comprises a capsule 20sized to be swallowed and pass through the intestinal tract, adeployment article 30, one or more tissue penetrating articles 40 (alsoreferred to as shell 40) containing a cell preparation 100 comprisingviable therapeutic cells 101, a deployable aligner 60 and a deliverymechanism 70. It should be appreciated that this is but one embodimentof a device for the delivery of viable cells 101 and that otherembodiments described herein are equally applicable including deviceswithout an aligner balloon 60.

The deployable aligner 60 is positioned within the capsule andconfigured to align the capsule with the intestine such as the smallintestine. Typically, this will entail aligning a longitudinal axis ofthe capsule with a longitudinal axis of the intestine; however, otheralignments are also contemplated. The delivery mechanism 70 isconfigured for delivering cell preparation 100 containing viabletherapeutic cells 101 into the intestinal wall and will typicallyinclude a delivery article 72 such as an expandable member. Thedeployment member 30 is configured for deploying at least one of thealigner 60 or the delivery mechanism 70. As will be described furtherherein, all or a portion of the capsule wall is degradable by contactwith liquids in the GI tract so as to allow those liquids to trigger thedelivery of viable cells 101 by device 10. As used herein, the term “GItract” refers to the esophagus, stomach, small intestine, largeintestine and anus, while “Intestinal tract” refers to the small andlarge intestine. Various embodiments of the invention can be configuredand arranged for delivery of preparation 100 comprising viabletherapeutic cells 101 into both the intestinal tract as well as theentire GI tract. Still other delivery cites are also consideredincluding various intramuscular sites.

Device 10 including tissue penetrating article 40 can be configured forthe delivery of liquid, semi-liquid or solid forms of preparation 100comprising viable cells 101 or combinations of all three. Whatever theform, article 40 desirably has a size, shape and material consistencyallowing the article to protect the viability of the cells 101 from theexternal environment (including that in the patient's GI tract prior todelivery); to be disposed in device 10/capsule 20; advanced out ofdevice 10 into the intestinal wall (small or large intestine),peritoneal wall or other wall or tissue site in the GI tract; and then,degrade (e.g. biodegrade) within the intestinal wall to release theviable cells 101 or other therapeutic agent. The material consistency ofarticle 40 can to performs these functions include one or more of thefollowing: hardness, porosity and solubility of the material componentscomprising article 40 in bodily fluids (e.g., interstitial fluids) Thematerial consistency can be achieved by selection and use of one or moreof the following properties and/or characteristics of the article: i)the compaction force used to make the article; ii) the use of one ormore pharmaceutical disintegrants known in the art; iii) use of otherpharmaceutical excipients; iv) the particle size and particledistribution within the article (e.g., the use of micronized particles);and v) use of micronizing and other particle formation methods known inthe art.

Typically, the device 10 and/or preparation 100 will be configured todeliver a single type of cell 101 as part of preparation 100. However insome embodiments, device 10 preparation 100 can be configured fordelivery of multiple cell types 101 including a first, second, or athird cell type which can be compounded into a single or multiple cellpreparations 100. For embodiments having multiple cell types, each celltype 101 can be contained in separate tissue penetrating members 40 orwithin separate compartments or reservoirs 27 within capsule 20. Inanother embodiment, a first dose 102 of cell preparation 100 containinga cell type 101 can be packed into the penetrating member(s) 40 and asecond dose 103 of cell preparation 100 (containing the same or adifferent cell 101) can be coated onto the surface 25 of capsule as isshown in the embodiment of FIG. 1B. The cell types 101 in the two dosesof preparations 102 and 103 can be the same or different. In this way, abimodal pharmacokinetic release of the same or different cells can beachieved.

In one or more embodiments, a system 11 for delivery of viabletherapeutic cells 101 into the wall of the small intestine or otherlocation within the intestinal tract or GI tract, may comprise device 10and an article 40 which contains preparations 100 comprising one or moreviable therapeutic cell types 101 for the treatment of a selecteddisease, condition or conditions. In some embodiments, the system mayinclude a hand held device 13, described herein for communicating withdevice 10 as is shown in the embodiment of FIG. 1B. In many embodiments,system 11 may also be configured as a kit 14 including system 11 and aset of instructions for use 15 which are packaged in packaging 12 as isshown in the embodiment of FIG. 1C. The instructions can indicate to thepatient when to take the device 10 relative to one or more events suchas the ingestion of a meal or a physiological measurement such as bloodglucose, cholesterol, etc. In such embodiments, kit 14 can includemultiple devices 10 containing a regimen of viable therapeutic cells 101for a selected period of administration, e.g., a day, week, or multipleweeks depending upon the condition to be treated (e.g., treatment ofcancer by a course of interferon treatment, treatment of an autoimmunedisease such as or psoriasis, multiple sclerosis or arthritis by immunesuppression agents).

According to various embodiments, capsule 20 is sized to be swallowedand pass through the intestinal tract. The size can also be adjusteddepending upon the amount of viable cells to be delivered as well as thepatient's weight and adult vs. pediatric applications. Typically, thecapsule will have a tubular shape with curved ends similar to a vitamin.In these and related embodiments, capsule lengths 20L can be in therange of 0.5 to 2 inches and diameters 20D in the range of 0.1 to 0.5inches with other dimensions contemplated. The capsule 20 includes acapsule wall 21 w, having an exterior surface 25 and an interior surface24 defining an interior space or volume 24 v. In some embodiments, thecapsule wall 21 w can include one or more apertures 26 sized for theoutward advancement of tissue penetrating articles 40 via needle lumen230. In addition to the other components of device 10, (e.g., theexpandable member etc.), the interior volume can include one or morecompartments or reservoirs 27.

The capsule can be fabricated from various biodegradable gelatinmaterials known in the pharmaceutical arts, but can also include variousenteric coatings 20 c, configured to protect the cap from degradation inthe stomach (due to acids etc.), and then subsequently degrade in the inhigher pH's found in the small intestine or other area of the intestinaltract. In various embodiments, the capsule 20 can be formed frommultiple portions one or more of which may be biodegradable. In manyembodiments, capsule 20 can be formed from two portions 20 p such as abody portion 20 p″ (herein body 20 p″) and a cap portion 20 p′ (hereincap 20 p′), where the cap fits onto the body, e.g., by sliding over orunder the body (with other arrangements also contemplated). One portionsuch as the cap 20 p′ can include a first coating 20 c′ configured todegrade above a first pH (e.g., pH 5.5) and the second portion such asthe body 20 p″ can include a second coating 20 c″ configured to degradeabove a second higher pH (e.g. 6.5). Both the interior 24 and exterior25 surfaces of capsule 20 are coated with coatings 20 c′ and 20 c″ sothat that either portion of the capsule will be substantially preserveduntil it contacts fluid having the selected pH. For the case of body 20p″ this allows the structural integrity of the body 20 p″ to bemaintained so as to keep balloon 72 inside the body portion and notdeployed until balloon 30 has expanded. Coatings 20 c′ and 20 c″ caninclude various methacrylate and ethyl acrylate based coatings such asthose manufactured by Evonik Industries under the trade name EUDRAGIT.These and other dual coating configurations of the capsule 20 allows formechanisms in one portion of capsule 20 to be actuated before those inthe other portion of the capsule. This is due to the fact thatintestinal fluids will first enter those portions where the lower pHcoating has degraded thus actuating triggers which are responsive tosuch fluids (e.g., degradable valves). In use, such dual coatingembodiments for capsule 20 provide for targeted viable cells delivery toa particular location in the small intestine (or other location in theGI tract), as well as improved reliability in the delivery process. Thisis due to the fact that deployment of a particular component, such asaligner 60, can be configured to begin in the upper area of the smallintestine (e.g., the duodenum) allowing the capsule to be aligned withinthe intestine for optimal delivery of the viable cells (e.g., into theintestinal wall) as well as providing sufficient time fordeployment/actuation of other components to achieve viable cellsdelivery into the intestinal wall while the capsule is still in thesmall intestine or other selected location.

As is discussed above, one or more portions of capsule 20 can befabricated from various biocompatible polymers known in the art,including various biodegradable polymers which in a preferred embodimentcan comprise cellulose, gelatin materials (PLGA) (polylactic-co-glycolicacid). Other suitable biodegradable materials include various entericmaterials described herein as well as lactide, glycolide, lactic acid,glycolic acid, para-dioxanone, caprolactone, trimethylene carbonate,caprolactone, blends and copolymers thereof.

Use of biodegradable materials for capsule 20, including biodegradableenteric materials allows the capsule to degrade in whole or part tofacilitate passage through the GI system before, during or after viablecells delivery. As is described in further detail herein, in variousembodiments, capsule 20 can include seams 22 of bio-degradable materialso as to controllably degrade into smaller pieces 23 which are moreeasily passed through the intestinal tract.

In various embodiments, the wall 20 w of the capsule is degradable bycontact with liquids in the GI tract for example liquids in the smallintestine. In preferred embodiments, the capsule wall is configured toremain intact during passage through the stomach, but then to bedegraded in the small intestine. In one or more embodiments, this can beachieved by the use of an outer coating or layer 20 c on the capsulewall 20 w, which only degrades in the higher pH's found in the smallintestine and serves to protect the underlying capsule wall fromdegradation within the stomach before the capsule reaches the smallintestine (at which point the viable cells delivery process is initiatedby degradation of the coating as is described herein). In use, suchcoatings allow for the targeted delivery of a therapeutic agent in aselected portion of the intestinal tract such as the small intestine.

In various embodiments, capsule 20 can include various radio-opaque,echogenic or other materials for location of the device using one ormore medical imaging modalities such as fluoroscopy, ultrasound, MRI,etc. In specific embodiments, all or a portion of the capsule caninclude radio-opaque/echogenic markers 20 m as is shown in theembodiment of FIGS. 1A and 1B. Suitable materials for radio-opaquemarkers 20 m include barium sulfate, compounds, titanium dioxide andcompounds thereof. In use, such materials allow for the location ofdevice 10 in the GI tract, as well as its state of deployment (e.g., adistinctive marker can be positioned on cap 20 p′ and another on body 20p″ allowing for determination if the deployment balloon 30 (discussedbelow) has inflated but the delivery balloon 72 has not). They can alsobe used allow for the determination of transit times of the devicethrough the GI tract. Such information can be used to titrate dosages ofviable cells for a particular patient, as well as provide information onwhen they should take particular viable cells after an event such asingestion of a meal in the case of insulin taken for treatment ofdiabetes. Markers 20 m can also be positioned on the capsule 20 to allowthe physician to determine if the capsule is intact, or has broken up.

As is discussed further herein, in many embodiments, one or more of thedeployment member 30, delivery member 72 or deployable aligner 60, maycorrespond to an expandable balloon that is shaped and sized to fitwithin capsule 20. Accordingly, for ease of discussion, deploymentmember 30, delivery member 72 and deployable aligner 60 will now bereferred to as balloon 30, 60 and 72; however, it should be appreciatedthat other devices including various expandable devices are alsocontemplated for these elements and may include for example, variousshape memory devices (e.g., an expandable basket made from shape memorybiodegradable polymer spires), expandable piezo electric devices, and/orchemically expandable devices having an expanded shape and sizecorresponding to the interior volume 24 v of the capsule 20.

One or more of balloons 30, 60 and 72 can comprise various polymersknown in the medical device arts. In preferred embodiments such polymerscan comprise one or more types of polyethylene (PE) which may correspondto low density PE (LDPE), linear low density PE (LLDPE), medium densityPE (MDPE) and high density PE (HDPE) and other forms of polyethyleneknown in the art. In one more embodiments using polyethylene, thematerial may be cross-linked using polymer irradiation methods known inthe art. In particular embodiments radiation-based cross-linking may beused as to control the inflated diameter and shape of the balloon bydecreasing the compliance of the balloon material. The amount orradiation may be selected to achieve a particular amount of crosslinking to in turn produce a particular amount of compliance for a givenballoon, e.g., increased irradiation can be used to produce stiffer lesscompliant balloon material. Other suitable polymers can include PET(polyethylene terephthalate), silicone and polyurethane. In variousembodiments balloons 30, 60 and 72 may also include various radio-opaquematerials known in the art such as barium sulfate to allow the physicianto ascertain the position and physical state of the balloon (e.g.,un-inflated, inflated or punctures. Balloons 30, 60 and 72 can befabricated using various balloon blowing methods known in the ballooncatheters arts (e.g., mold blowing, free blowing, etc.) to have a shapeand size which corresponds approximately to the interior volume 24 v ofcapsule 20. In various embodiments one or more of balloons 30, 60 and 72and various connecting features (e.g., connecting tubes) can have aunitary construction being formed from a single mold. Embodimentsemploying such unitary construction provide the benefit of improvedmanufacturability and reliability since fewer joints must be madebetween one or more components of device 10.

Suitable shapes for balloons 30, 60 and 72 include various cylindricalshapes having tapered or curved end portions (an example of such a shapeincluding a hot dog). In some embodiments, the inflated size (e.g.,diameter) of one or more of balloons 30, 60 and 72, can be larger thancapsule 20 so as to cause the capsule to come apart from the force ofinflation, (e.g., due to hoop stress). In other related embodiments, theinflated size of one or more of balloons 30, 60 and 72 can be such thatwhen inflated, i) the capsule 20 has sufficient contact with the wallsof the small intestine so as to elicit a peristaltic contraction causingcontraction of the small intestine around the capsule, and/or ii) thefolds of the small intestine are effaced to allow contact. Both of theseresults allow for improved contact between the capsule/balloon surfaceand the intestinal wall so as deliver tissue penetrating articles 40over a selected area of the capsule and/or delivery balloon 72.Desirably, the walls of balloons 30, 60 and 72 will be thin and can havea wall thickness in the range of 0.005 to 0.0001″ more preferably, inthe range of 0.005 to 0.0001, with specific embodiments of 0.004, 0.003,0.002, 0.001, and 0.0005). Additionally in various embodiments, one ormore of balloon 30, 60 or 72 can have a nested balloon configurationhaving an inflation chamber 60IC and extended finger 60EF as is shown inthe embodiments of FIG. 3C. The connecting tubing 63, connecting theinflation chamber 60IC can be narrow to only allow the passage of gas68, while the connecting tubing 36 coupling the two halves of balloon 30can be larger to allow the passage of water.

As indicated above, the aligner 60 will typically comprise an expandableballoon and for ease of discussion, will now be referred to as alignerballoon 60 or balloon 60. Balloon 60 can be fabricated using materialsand methods described above. It has an unexpanded and expanded state(also referred to as a deployed state). In its expanded or deployedstate, balloon 60 extends the length of capsule 20 such that forcesexerted by the peristaltic contractions of the small intestine SI oncapsule 20 serve to align the longitudinal axis 20LA of the capsule 20in a parallel fashion with the longitudinal axis LAI of the smallintestine SI. This in turn serves to align the shafts of tissuepenetrating articles 40 in a perpendicular fashion with the surface ofthe intestinal wall IW to enhance and optimize the penetration of tissuepenetrating articles 40 into the intestinal wall IW. In addition toserving to align capsule 20 in the small intestine, aligner 60 is alsoconfigured to push delivery mechanism 70 out of capsule 20 prior toinflation of delivery balloon 72 so that the delivery balloon and/ormechanism is not encumbered by the capsule. In use, this push outfunction of aligner 60 improves the reliability for delivery of thetherapeutic agent since it is not necessary to wait for particularportions of the capsule (e.g., those overlying the delivery mechanism)to be degraded before viable cells delivery can occur.

Balloon 60 may be fluidically coupled to one or more components ofdevice 10 including balloons 30 and 72 by means of polymer tube or otherfluidic couplings 62 which may include a tube 63 for coupling balloons60 and 30 and a tube 64 for coupling balloon 60 and balloon 72. Tube 63is configured to allow balloon 60 to be expanded/inflated by pressurefrom balloon 30 (e.g., pressure generated the mixture of chemicalreactants within balloon 30) and/or otherwise allow the passage ofliquid between balloons 30 and 60 to initiate a gas generating chemicalreaction for inflation of one or both of balloons 30 and 60. Tube 64connects balloon 60 to 72 so as to allow for the inflation of balloon 72by balloon 60. In many embodiments, tube 64 includes or is coupled to acontrol valve 55 which is configured to open at a selected pressure soas to control the inflation of balloon 72 by balloon 60. Tube 64 maythus comprise a proximal portion 64 p connecting to the valve and adistal portion 64 d leading from the valve. Typically, proximal anddistal portions 64 p and 64 d will be connected to a valve housing 58 asis described below.

Valve 55 may comprise a triangular or other shaped section 56 of amaterial 57 which is placed within a chamber 58 c of a valve housing 58(alternately, it may be placed directly within tubing 64). Section 57 isconfigured to mechanically degrade (e.g., tears, shears, delaminates,etc.) at a selected pressure so as to allow the passage of gas throughtube 64 and/or valve chamber 58 c. Suitable materials 57 for valve 55can include bees wax or other form of wax and various adhesives known inthe medical arts which have a selectable sealing force/burst pressure.Valve fitting 58 will typically comprise a thin cylindrical compartment(made from biodegradable materials) in which section 56 of material 57is placed (as is shown in the embodiment of FIG. 3B) so as to seal thewalls of chamber 58 c together or otherwise obstruct passage of fluidthrough the chamber. The release pressure of valve 55 can be controlledthrough selection of one or more of the size and shape of section 56 aswell as the selection of material 57 (e.g., for properties such asadhesive strength, shear strength etc.). In use, control valve 55 allowsfor a sequenced inflation of balloon 60 and 72 such that balloon 60 isfully or otherwise substantially inflated before balloon 72 is inflated.This, in turn, allows balloon 60 to push balloon 72 along with the restof delivery mechanism 70 out of capsule 20 (typically from body portion20 p′) before balloon 72 inflates so that deployment of tissuepenetrating articles 40 is not obstructed by capsule 20 In use, such anapproach improves the reliability of the penetration of tissuepenetrating articles 40 into intestinal wall IW both in terms ofachieving a desired penetration depth and delivering greater numbers ofthe penetrating articles 40 contained in capsule 20 since theadvancement of the articles into intestinal wall IW is not obstructed bycapsule wall 20 w.

As is describe above, the inflated length 60 l of the aligner balloon 60is sufficient to have the capsule 20 become aligned with the lateralaxis of the small intestine from peristaltic contractions of theintestine. Suitable inflated lengths 60 l for aligner 60 can include arange between about ½ to two times the length 201 of the capsule 20before inflation of aligner 60. Suitable shapes for aligner balloon 60can include various elongated shapes such as a hotdog like shape. Inspecific embodiments, balloon 60 can include a first section 60′ and asecond section 60″, where expansion of first section 60′ is configuredto advance delivery mechanism 70 out of capsule 20 (typically out of andsecond section 60″ is used to inflate delivery balloon 72. In these andrelated embodiments, first and second sections 60′ and 60″ can beconfigured to have a telescope-style inflation where first section 60′inflates first to push mechanism 70 out of the capsule (typically frombody portion 20 p′) and second section 60″ inflates to inflate deliverymember 72. This can be achieved by configuring first section 60′ to havesmaller diameter and volume than second section 60″ such that firstsection 60′ inflates first (because of its smaller volume) and withsecond section 60″ not inflating until first section 60′ hassubstantially inflated. In one embodiment, this can be facilitated byuse of a control valve 55 (described above) connecting sections 60′ and60″ which does not allow passage of gas into section 60″ until a minimumpressure has been reached in section 60′. In some embodiments, thealigner balloon can contain the chemical reactants which react uponmixture with water or other liquid from the deploying balloon.

In many embodiments, the deployment member 30 will comprise anexpandable balloon, known as the deployment balloon 30. In variousembodiments, deployment balloon 30 is configured to facilitatedeployment/expansion of aligner balloon 60 by use of a gas, for example,generation of a gas 69 from a chemical. The gas may be generated by thereaction of solid chemical reactants 65, such as an acid 66 (e.g.,citric acid) and a base 67 (e.g., potassium bicarbonate, sodiumbicarbonate and the like) which are then mixed with water or otheraqueous liquid 68. The amount of reactants may be chosen usingstoichiometric methods to produce a selected pressure in one or more ofballoons 30, 60 and 72. The reactants 65 and liquids can be storedseparately in balloon 30 and 60 and then brought together in response toa trigger event, such as the pH conditions in the small intestine. Thereactants 65 and liquids 68 can be stored in either balloon, however inpreferred embodiments, liquid 68 is stored in balloon 30 and reactants65 in balloon 60. To allow for passage of the liquid 68 to start thereaction and/or the resulting gas 69, balloon 30 may be coupled toaligner balloon 60 by means of a connector tube 63 which also typicallyincludes a separation means 50 such as a degradable valve 50 describedbelow. For embodiments where balloon 30 contains the liquid, tube 63 hassufficient diameter to allow for the passage of sufficient water fromballoon 30 to balloon 60 to produce the desired amount of gas to inflateballoon 60 as well inflate balloon 72. Also when balloon 30 contains theliquid, one or both of balloon 30 and tube 63 are configured to allowfor the passage of liquid to balloon 60 by one or more of the following:i) the compressive forced applied to balloon 30 by peristalticcontractions of the small intestine on the exposed balloon 30; and ii)wicking of liquid through tube 63 by capillary action.

Tube 63 will typically include a degradable separation valve or otherseparation means 50 which separates the contents of balloon 30, (e.g.,water 58) from those of balloon 60 (e.g., reactants 65) until the valvedegrades. Valve 50 can be fabricated from a material such as maltose,which is degradable by liquid water so that the valve opens uponexposure to water along with the various liquids in the digestive tract.It may also be made from materials that are degradable responsive to thehigher pH's found in the intestinal fluids such as methacrylate basedcoatings. The valve is desirably positioned at location on tube 63 whichprotrudes above balloon 30 and/or is otherwise sufficient exposed suchthat when cap 20 p′ degrades the valve 50 is exposed to the intestinalliquids which enter the capsule. In various embodiments, valve 50 can bepositioned to lie on the surface of balloon 30 or even protrude above it(as is shown in the embodiments of FIGS. 6A and 6B), so that is hasclear exposure to intestinal fluids once cap 20 p′ degrades. Variousembodiments of the invention provide a number of structures for aseparation valve 50, for example, a beam like structure (where the valvecomprises a beam that presses down on tube 63 and/or connecting section36), or collar type structure (where the valve comprises a collar lyingover tube 63 and/or connecting section 36). Still other valve structuresare also contemplated.

Balloon 30 has a deployed and a non-deployed state. In the deployedstate, the deployment balloon 30 can have a dome shape 30 d whichcorresponds to the shape of an end of the capsule. Other shapes 30 s forthe deployed balloon 30 are also contemplated, such as spherical,tube-shape, etc. The reactants 65 will typically include at least tworeactants 66 and 67, for example, an acid such as citric acid and a basesuch as sodium bicarbonate, which can have about a 1:2 ratio. Otherreactants 65 including other acids, e.g., ascetic acid and bases, e.g.,sodium hydroxide are also contemplated. When the valve or otherseparation means 50 opens, the reactants mix in the liquid and produce agas such as carbon dioxide which expands the aligner balloon 60 or otherexpandable member.

In an alternative embodiment shown in FIG. 3B, the deployment balloon 30can actually comprise a first and second balloon 30′ and 30″ connectedby a tube 36 or other connection means 36 (e.g., a connecting section).Connecting tube 36 will typically include a separation valve 50 that isdegradable by a liquid as described above and/or a liquid having aparticular pH such as basic pH found in the small intestine (e.g., 5.5or 6.5). The two balloons 30′ and 30″ can each have a half dome shape 30hs allowing them to fit into the end portion of the capsule when in theexpanded state. One balloon can contain the chemical reactant(s) 65(e.g., sodium bicarbonate, citric acid, etc.) the other the liquid water68, so that when the valve is degraded the two components mix to form agas which inflates one or both balloons 30′ and 30″ and in turn, thealigner balloon 60.

In yet another alternative embodiment, balloon 30 can comprise amulti-compartment balloon 30 mc, that is formed or other constructed tohave multiple compartments 30 c. Typically, compartments 30 c willinclude at least a first and a second compartment 34 and 35 which areseparated by a separation valve 50 or other separation means 50 as isshown in the embodiment of FIG. 4A. In many embodiments, compartments 34and 35 will have at least a small connecting section 36 between themwhich is where separation valve 50 will typically be placed. A liquid68, typically water, can be disposed within first compartment 34 and oneor more reactants 65 disposed in second compartment 35 (which typicallyare solid though liquid may also be used) as is shown in the embodimentof FIG. 4A. When valve 50 opens (e.g., from degradation caused by fluidswithin the small intestine) liquid 68 enters compartment 35 (or viceversa or both), the reactant(s) 65 mix with the liquid and produce a gas69 such as carbon dioxide which expands balloon 30 which in turn can beused to expand one or more of balloons 60 and 72.

Reactants 65 will typically include at least a first and a secondreactant, 66 and 67 for example, an acid such as citric acid and a basesuch as sodium bi-carbonate or potassium bi-carbonate. As discussedherein, in various embodiments they may be placed in one or more ofballoon 30 (including compartments 34 and 35 or halves 30′ and 30″) andballoon 60. Additional reactants, including other combinations of acidsand bases which produce an inert gas by product are also contemplated.For embodiments using citric acid and sodium or carbonate, the ratiosbetween the two reactants (citric acid to potassium bicarbonate) can bein the range of about 1:1 to about 1:4, with a specific ratio of about1:3. Desirably, solid reactants 65 have little or no absorbed water.Accordingly, one or more of the reactants, such as sodium bicarbonate orpotassium bicarbonate can be pre-dried (e.g., by vacuum drying) beforebeing placed within balloon 30. Other reactants 65 including otheracids, e.g., ascetic acid and bases are also contemplated. The amountsof particular reactants 65, including combinations of reactants can beselected to produce particular pressures using known stoichiometricequations for the particular chemical reactions as well as the inflatedvolume of the balloon and the ideal gas law (e.g., PV=nRT). Inparticular embodiments, the amounts of reactants can be selected toproduce a pressure selected one or more of balloons 30, 60 and 72 to i)achieve a particular penetration depth into the intestinal wall; ii) andproduce a particular diameter for one or more of balloons 30, 60 and 72;and iii) exert a selected amount of force against intestinal wall IW. Inparticular embodiments, the amount and ratios of the reactants (e.g.,citric acid and potassium bicarbonate) can be selected to achievepressures in one more of the balloons 30, 60 and 72 in the range of 10to 15 psi, with smaller and larger pressures contemplated. Again theamounts and ratios of the reactants to achieve these pressures can bedetermined using known stoichiometric equations.

In various embodiments of the invention using chemical reactants 65 togenerate gas 69, the chemical reactants alone or in combination with thedeployment balloon 30 can comprise a deployment engine for 80 deployingone or both of the aligner balloon 60 and delivery mechanism 70including delivery balloon 72. Deployment engine 80 may also includeembodiments using two deployment balloons 30 and 30″ (a dual domeconfiguration as shown in FIG. 3B), or a multi compartment balloon 30 mcas shown in FIG. 4A. Other forms of a deployment engine 80 are alsocontemplated by various embodiments of the invention such as use ofexpandable piezo-electric materials (that expand by application of avoltage), springs and other shape memory materials and various thermallyexpandable materials.

One or more of the expandable balloons 30, 60 and 72 will also typicallyinclude a deflation valve 59 which serves to deflate the balloon afterinflation. Deflation valve 59 can comprise biodegradable materials whichare configured to degrade upon exposure to the fluids in the smallintestine and/or liquid in one of the compartments of the balloon so asto create an opening or channel for escape of gas within a particularballoon. Desirably, deflation valves 59 are configured to degrade at aslower rate than valve 50 to allow sufficient time for inflation ofballoons, 30, 60 and 72 before the deflation valve degrades. In variousembodiments, of a compartmentalized balloon 30, deflation valve 59 cancorrespond to a degradable section 39 positioned on an end portion 31 ofthe balloon as is shown in the embodiment of FIG. 4A. In this andrelated embodiments, when degradable section 39 degrades from exposureto the liquid, balloon wall 32 tears or otherwise comes apart providingfor a high assurance of rapid deflation. Multiple degradable sections 39can be placed at various locations within balloon wall 32.

In various embodiments of balloon 72, deflation valve 59 can correspondto a tube valve 73 attached to the end 72 e of the delivery balloon 72(opposite to the end which is coupled to the aligner balloon) as isshown in the embodiment of FIG. 3B. The tube valve 73 comprises a hollowtube 73 t having a lumen that is obstructed at a selected location 73 lwith a material 73 m such as maltose that degrades upon exposure tofluid such as the fluid in the small intestine. The location 73 l of theobstructing material 73 m in tube 73 t is selected to provide sufficienttime for the delivery balloon 72 to inflate and deliver the tissuepenetrating articles 40 into the intestinal wall IW before theobstructing material dissolves to open valve 73. Typically, this will beclose to the end 73 e of the tube 73 t, but not quite so as to allowtime for liquid to have to wick into the tube lumen before it reachesmaterial 73 m. According to one or more embodiments, once the deflationvalve 73 opens, it not only serves to deflate the delivery balloon 72but also the aligner balloon 60 and deployment balloon 30 since in manyembodiments, all three are fluidically connected (aligner balloon beingfluidically connected to delivery balloon 72 and the deployment balloon30 being fluidically connected to aligner balloon 60). Opening of thedeflation valve 73 can be facilitated by placing it on the end 72 e ofthe delivery balloon 72 that is forced out of capsule 20 by inflation ofthe aligner balloon 60 so that the deflation valve has good exposure toliquids in the small intestine. Similar tube deflation valves 73 canalso be positioned on one or both of aligner balloon 62 and thedeployment balloon 30. In these later two cases, the obstructingmaterial in the tube valve can be configured to degrade over a timeperiod to allow sufficient time for inflation of delivery balloon 72 andadvancement of tissue penetrating articles 40 into the intestinal wall.

Additionally, as further backup for insured deflation, one or morepuncture elements 82 (shown in FIG. 2A) can be attached to the insidesurface 24 of the capsule such that when a balloon (e.g., balloon 30,60, 72) fully inflates it contacts and is punctured by the punctureelement 82. Puncture elements 82 can comprise short protrusions fromsurface 24 having a pointed tip. In another alternative or additionalembodiment of a means for balloon deflation, one or more of the tissuepenetrating articles 40 can be directly coupled to the wall of 72 w ofballoon 72 and configured to tear away from the balloon when theydetach, tearing the balloon wall in the process.

With specific reference to the inventions claimed herein, tissuepenetrating articles (TPA) 40 and 40′ are illustrated in FIGS. 8A and8B. A first exemplary TPA 40 (FIG. 8A) includes a shell 42 having atissue-penetrating distal tip 44 and a proximal base 45. Thetissue-penetrating distal tip 44 may comprise a generally conicalstructure, as illustrated, with a pointed tip that can penetrate intotissue when a propulsive force is applied to the proximal base 45 in adirection toward the tip (as indicated by arrows 48). Optionally, acoupling structure 47 will be provided on the end surface of the base toengage the TPA with the propulsion capsules described herein. The shellcan be fabricated by one or more of molding, machining, dip-casting andother polymer fabrications methods known in the art. Further accordingto specific embodiments, the shells including embodiments havingfenestrations described below can be fabricated using various3D-printing methods known in the art. Use of 3-Printing provides thebenefit of increased accuracy and precision of the dimensions of the TPAalong with reduced contamination, fabrication time and cost.

In the embodiment of FIG. 8A, the shell or barrier 42 will have agenerally impermeable wall 46 which biodegrades over time in a tissueenvironment, such as an intestinal tissue environment, typically withinthe exemplary time periods set forth earlier in this application.According to various embodiments, the biodegradable shell 42 may beformed from a biodegradable metal, such as magnesium, iron, zinc, or thelike, or from a biodegradable polymer, such as poly lactic acid (PLA),poly(lactic-co-glycolic acid) (PLGA), or the like. In all cases, thebiodegradable shell will have sufficient durability (e.g. in terms ofstructural integrity) so that the shell remains intact to protect theviable cells (e.g. dose 102 of cell preparation 100 containing a celltype 101) being delivered until the article has been implanted in atarget tissue site in the GI tract or other location. The time it takesfrom introduction to the patient until the shell erodes sufficiently toexpose and/or release the viable cells can be selected based on variousfactors including the particular materials and construction of theshell. In one or more embodiments, the biodegradation time can beprogrammed or otherwise controlled by selection of one or more of thefollowing: i) shell material selection (e.g., particular bioerodablepolymers); ii) shell wall thickness; iii) the inclusion pits or othererosion initiation sites on the shell surface so as to providesacrificial layers over the shell, or the like

Embodiments of the invention are useful for orally delivering a varietyof cells in viable condition to a human patient or other mammaliananimal. The viable cells can include those used for both therapeutic anddiagnostic purposes. For example, the cells can include those whichproduce therapeutic agents such as insulin or various incretins, stemcells which differentiate into selected cells or cells for seeding orreseeding a selected tissue site such as the mucosa at one or morelocations in the GI tract. Embodiments of the invention are beparticularly useful for delivering viable pancreatic beta cells or otherpancreatic entero-endocrine cells to the patient's digestive organ orintestinal tissue so that the cells can produce insulin for thetreatment of diabetes or other glucose control conditions. Suchpancreatic enter-endocrine cells can be delivered to the pancreas or insome cases to the small intestine where the cells are seeded and becomeincorporated into the intestinal wall so as to release insulin into theblood stream from the small intestine.

Embodiments of the invention are not limited however, to the delivery ofbeta cells, but rather can be used to deliver a variety of other viablecell masses to a patient for the treatment of a variety of conditions aswell as for diagnostic purposes. Other exemplary viable cells to bedelivered include without limitation, human and other stem cells,specifically including mesenchymal stem cells and hematopoietic stemcells; Gastric entero-endocrine cells such as G-cells; or Intestinalenter-endocrine cells such as L-cells K-cells, I-cells, N-cells andS-cells. They may also various mucosal cells, includinggastro-intestinal mucosal cells for purposes of reseeding the mucosallining of the stomach or small intestine; and differentiated cells,including those of the immune system including lymphocytes such asT-cells, B-cells and Killer cells; and Granulocytes such as neutrophilseosinophils and monocytes, and the like.

In other embodiments, the invention provides methods whereby the patienttakes swallowable articles containing viable cells to reseed selectedportions of the GI tract with cells such as hormone or other peptideproducing cells that produce a therapeutic effect. For example accordingto one or more embodiments the invention provides methods whereby thesmall intestine or other location in the GI tract are reseeded withL-cells or K-cells to produce incretin or G-cells to produce Gastrin. Inspecific embodiments, the cells can comprise various mucosal cells toreseed the mucosa of the stomach, pylorus and duodenum for example totreat one or more of a gastric, pyloric or duodenal ulcer or loss ofsuch cells due to cancer or chemotherapeutic treatment thereof. Further,the articles can be configured to reseed specific portions of specificGI organs such as the duodenum or jejunum of the small intestine and thepyloric region of the stomach. The articles can be configured to injectcells into theses specific regions by the use of pH sensitive coatingsdescribed herein such as various EUDRAGIT coatings and others known inthe art which degrade in response to specific pH's in specific location,such as more acid pH in the stomach (1.5-3.5) and increasingly lessacidic pH in the small intestine (5.5 in the duodenum and 6.5-6.8 in thejejunum).

According to one or more embodiments, the cells to be delivered aredesirably maintained within a protected interior of the TPA suspended ina viability-sustaining gel 49. Such gels are well known in the art anddescribed in the medical and patent literature. A suitable gel maycomprise a gelatin, typically at a weight percentage that ranges fromabout 4 to about 20 weight %, usually between about 5-10 weight % of thetotal weight of the gel (similar volume percentages may also beconsidered. In various embodiments, the gelatin may be replaced orsupplemented with one or more of collagen, fibrin, fibrinogen, albumin,and keratin and/or other glutamine/lysine rich peptides atconcentrations which foster cell viability. In various embodiments gels49 may be injected into the shells, may be a precast gel (e.g., put inplace before the shell is completely formed), or may be provided asbeads or micelles. The gel will typically be a hydrogel and in manyembodiment, may be frozen or chilled within the shell prior to use. Thehydrogel will usually be consumed over time by the cells being supportedby the gel, but such consumption will be held in abeyance by freezingand/or reduced by maintaining the cells at chilled temperatures (e.g. 33to 45° F., though other temperature ranges are also contemplated).

In other embodiments, the gel may correspond to a protein-based hydrogelwith a crosslinking agent that is mixed in with the gel. Also, inparticular embodiments, the gel may contain oxygen (by being partiallyor fully saturated with the gas) prior to filling or after filling inthe shell to further enhance the viability sustaining properties of thegel. In other embodiments, the gel may contain nitrogen or other inertgas so as to enhance preservation of the cells prior to use. In relatedembodiments, the gel can contain both oxygen and nitrogen or other inertgas. The particular amount of saturation of such gases can be selectedbased upon one or more of the intended shelf life of the swallowablecapsule containing the viable cells and the storage conditions (e.g.,whether the capsule 10 or TPA 40 is stored at room temperature,refrigerated below room temperature or frozen). According to variousembodiments the saturation level of oxygen in the gel can range fromabout 5 to 100%, with specific embodiments of 10, 20, 25, 30, 40, 50,60, 70, 80, 90 and 95%). The saturation level for nitrogen or otherinert gas in the gel can have similar values.

According to particular embodiments, the hydrogel may correspond to atransglutaminase that is reactive with fibrin, fibrinogen, collagen,albumen, involucrin, or gelatin. Protein gels can be combined withglycosaminoglycan (GAG) or proteoglycans such as, but no limited tohyaluronic acid, chondroitin sulfate, heparin, and keratin sulfate.Protein gels can also be combined with polysaccharides, such as, but notlimited to starch, cellulose, methylcellulose, alginate, agarose, chitinor chitosan, glycogen, xanthan gum, dextran, welan gum, gellan gum,diutan gum, and pullulan. Protein gels can be also combined with fattysubstance such as, but not limited to lecithin. Protein gels can be alsocombined with synthetic polymers such as, but not limited to PEG(polyethylene glycol). See for example, US Patent Publication No.2010/0215715 (the full disclosure of which is incorporated herein byreference for all purposes) for further explanation of how this may bedone.

As discussed herein in many embodiments, the invention provides methodsfor delivery of viable cells into solid tissue of a patient such as thatin the gastro intestinal tract, wherein the cells are put into areversible suspended state of animation prior to being administered tothe patient including prior to being put into the article wherein theyreanimate after being delivered to the patient so as to produce adesired therapeutic effect. Such therapeutic effects can includeexample, producing one or more therapeutic compounds (e.g., insulin,integrin, etc.). Suspended animation also includes states of slowedcellular animation wherein the cellular metabolism and processes aresignificantly slowed. Typically the cells will be put into the state ofsuspended or slowed state of animation by freezing or chilling the cellsand/or the gel containing them within the article prior to administeringthe article to the patient. Chilling may be done to a temperature in therange of 50 to 33° F. with a preferred range of 39 to 40° F. In analternative or variation, the cells and/or gel containing them may befrozen or chilled prior to being placed into the article. Freezing thearticles and the cells therein prior to administration is particularlyuseful as it can preserve the cells for extended periods of time in areversible state of suspended animation without the need to supplynutrients and remove cellular products. Similar results can be achievedby chilling the cells as well. Once the articles are administered to thepatient, however, the cells will thaw and warm within a short timeperiod to become reanimated and resume cellular processes. For certaincells, reanimation of the cells results in the cells resuming productionof various therapeutic by-products depending upon the cell (e.g.insulin, incretin, gastrin, etc.). Depending upon the cell and theparticular type of suspended animation process (freezing, chilling,freeze drying etc.), reanimation can be further facilitated or mayinitially occur by insertion of the cells into the patient's tissue suchas the wall of the small intestine so as to provide them access to bloodsupply bringing them nutrients and carrying away waste products. Othermethods of producing suspended reversible animation of the viable cellsare also contemplated besides freezing and chilling. These may includefor example, use of certain compounds in the gel and/or charging the gelwith an inert gas (e.g., nitrogen) and lyophilizing of the cells (orother freeze drying methods) prior to administration. In the case oflyophilizing or other freeze drying method, re-animation can be broughtabout by insertion of the cells into or brought in contact with thepatient's solid tissue (e.g. such as into the walls of the smallintestine or other location in the intestinal tract) where the cells arewarmed, rehydrated by the patient's interstitial fluids and exposed tothe patient's blood supply to bring the cells nutrient's and carry awaywaste products (e.g. CO2, etc.). Embodiments of the inventioncontemplate a number of different cell types that can be lyophilized soas to be put into a reversible state of suspended animation includingfor example, stem cells, mesenchymal stem cells, L-cells, K-cells,G-cells, Beta-Cells and the like. Specific description of methodologyfor lyophilization of stem cells and other cell types may be found in apaper by Zhang, et al, entitled, “Preliminary study on the freeze-dryingof human bone marrow-derived mesenchymal stem cells” J Zhejiang Univ SciB. 2010 November; 11(11): 889-894 which is incorporated herein for allpurposes. Once the cells are kept put into the reversible suspendedstate of animation, they may be kept in that state during oral deliveryby enclosed by various embodiments of the tissue penetrating articledescribed herein. The article can be configured to protect the cellsfrom various body fluids, particularly those in gastrointestinal tractwhich may lyse or otherwise damage the cells or bring them out of theirstate of suspended animation before they can be delivered to theirintended target tissue site (e.g., into the walls of the smallintestine). Once the article is inserted into the target tissue site, itcan be configured to biodegrade as described herein so as to bring thecells into contact with body fluids (e.g., blood, interstitial fluid,etc.) which reanimate the cells bringing them out of their state ofsuspended animation. In the case of frozen or chilled cells, the articlecan also be configured to provide a degree of thermal insulationincluding during oral delivery to prevent or slow unwanted reanimationof the cells from thawing and/or rewarming. In alternative or additionalembodiments, the article can be configured to be degrade or otherwise bebroken down to release their payload of cells by the external delivery(e.g. outside the body) of energy such as RF or acoustical energy (e.g.,using RF electrodes or piezo electric crystals for ultrasonic or otheracoustical energy). In this way the patient or medical provider canrelease the cells to the intended delivery site on demand.

For orally delivered frozen or otherwise suspended cells, once the cellsare reanimated (e.g. by the patient's body heat) they may be at risk ofdegradation during oral delivery from the gastrointestinal environment.Accordingly, in various embodiments of the shell described herein can beconfigured to protect the now metabolically active cells as they passthrough a patient's gastrointestinal tract where they would be exposedto the digestive conditions of the stomach which, without protection,would quickly kill the cells. Once penetrated into the intestinal tract,the article will be implanted into the intestinal tissue, thus releasingthe viable cells where they are now in an environment in which cellviability can be maintained and they can generate the useful therapeuticsubstances which they produce. Embodiments of these methods employarticles which may have the preferred characteristics and dimensionsdiscussed above in connection with articles of the present invention.

FIG. 8B illustrates an alternative embodiment of a TPA 40′ including ashell or barrier 42′ and a tissue-penetrating distal tip 44″. Incontrast to the TPA 40, TPA 40′ has a shell wall 46′ that hasfenestrations 47′, i.e. small holes or apertures, which are sized toallow exchange of fluids (indicated by arrows 48′) and molecules (suchas those produced by viable cells 101) with the tissue embodiment butwhich retain and protect the cells and the supporting gels 49′ withinthe interior of the shell. When the shell 42′ has such fenestrations47′, it will not always be necessary that the shell wall 46′ be fully oreven partially biodegradable since the cells can receive oxygen andnutrients from the surrounding tissue which diffuse in through thefenestrations and release therapeutically useful metabolites and othercellular products (e.g. insulin, integrins, Gastrin, etc.) into thetissue by diffusion out through the fenestrations. Usually, however, itwill be preferable that even the fenestrated walls be biodegradable overa selected time period (e.g. days, weeks, months etc.). Thefenestrations can be produced by various methods known in the polymerand other material science arts including, for example, solvent methods(e.g., solvent dissolution), laser drilling, and 3-D printing methodsknown in the art.

In various embodiments, the fenestrations 47′ can have a diametercorrelated to a major diameter or other major dimension of theparticular cell or cells contained within the article. In particularembodiments the fenestrations diameter can be matched to a selectedpercentage (e.g., 1, 5, 10, 25, 50% etc.) of the major cell dimension.The fenestrations 47′ will typically have a width in the range fromabout 0.1 to 15 μm more preferably about 0.5 to 5 μm and/or an area inthe range from 0.03 to 707 μm² , more preferably about 0.79 to 79 μm².According so some embodiments, when the shell comprises fenestrations,it may be formed from a non-biodegradable material since many cells canmaintain viability through fluid and substance exchange with theimplanted tissue and can release therapeutically useful cell products tothe tissue through the same fenestrations. Usually, however, even withfenestrations, it will be preferable to form the shell wall 46′ from thebiodegradable material. In alternative or additional embodiment, thefenestrations may be configured to produce a distinct acousticalsignature or pattern when pinged by an external acoustical transceiversuch as an ultrasound transceiver or other piezo electric basedacoustical transceiver and thus function as markers 47 m (e.g.,echogenic markers) when imaged ultrasonically or by other acousticalimaging modality or sensing modality. Further as the fenestrations breakdown due to bio-erosion of the article, the acoustical signature ofshell in response to an acoustical ping changes such the degree ofbio-erosion of the shell can be discerned. In particular embodiments thefenestrations can be configured to produce distinct acoustical patternswhen there is no bio-erosion, and when there is 25, 50 and 75%bio-erosion etc. and thus provide indicia 47 i of the degree ofdegradation of the shell. In this way, the fenestrations provideactionable information for the user to know when the article/shell hasdegraded sufficiently to release the cells to the selected tissue site.The specific acoustical signatures can be produced by the size andspacing of the fenestrations so to produce a specific acousticalreflective pattern. In specific embodiments this can be achieved bycorrelating one or both of the fenestration diameter or spacing towavelength of the particular acoustical signal used to ping thefenestration. In alternative or additional embodiments for providinginformation on the state of degradation of the articles, the articlescan include other acoustical markers 47 m′ or indicia 47 c configured toprovide specific acoustical signatures of the percent degradation of thearticle.

Referring now to FIG. 8C, in another embodiment of a TPA, indicated as40″ (with the other common element numbers staying the same as FIG. 8Afor ease of writing), the TPA can including a moisture barrier 42 b onan interior surface 42cs of the shell 42. The moisture barrier isconfigured to slow or prevent degradation of shell 42 and shell wall 46from any moisture from preparation 100 including from gel 49. In use thebarrier 42 b serves to improve the shelf life of the shell 42 and TPA40″ by preventing such degradation. Once the shell wall 42 degrades fromthe outside such the barrier 42 b is no longer fully mechanicallysupported by wall 46, the barrier is configured to shear or otherwisemechanically fail due to forces imparted on the coating from tissuewithin the body (e.g. from peristaltic contraction, breathing, bloodflow organ movement etc.). This can be achieved through the choice ofmaterial for the barrier and its thickness, for example thickness of thebarrier 42 b can range from about 0.01 to 0.001″. Thinner coatings beingmore susceptible to shearing from internal body forces and/or fromforces resulting from degradation of the shell 42 (e.g. when pieces ofthe shell come off). In preferred embodiments, the barrier 42 bcomprises a coating 42 bc including various water impermeable polymercoatings known in the art. Coating 42 bc may applied using variousspray, dip coating and plasma deposition methods known in the art. Inone embodiment coating 42 bc may comprise a butyl rubber known in themedical material arts.

Referring now to FIG. 8D, in another embodiment of the TPA indicate asTPA as TPA ″′ (all other element number staying the same), article 40″′can include an shock absorbing structure 47 s positioned on a bottominterior surface of the shell wall 46 (the bottom surface being at theopposite end from distal tip 44). Shock absorbing structure 47 s maycomprise various biodegradable elastomers known in the art and isconfigured to absorb and reduce the force imparted from bottom surface45 to preparation 100 including cells 101 when a propulsion force isimparted to the bottom surface to propel the article 40″′ into tissue.The imparted force is desirably reduced sufficiently to reduce orprevent any damage or injury to cells 101, 103 in preparation 100. Invarious embodiments the shock absorber 47 s can be configured to reducethe force transmitted to preparation 100 cells 101 to less than 0.2 lbsmore preferably less than 0.1 lbs and still more preferably less than0.05 lbs. Such force reductions can be obtained by selection of thethickness and durometer of the shock absorber 47 s. In relatedembodiments the viscoelastic properties of gel 49 can be selected suchthat the gel acts as a shock absorbing medium 49 s to reduce theaforementioned forces imparted to cells 101 from article propulsion asdescribed above. Suitable viscoelastic properties of the gel which canbe selected to achieve force reduction can include one or more ofviscosity and storage modulus (G). In particular embodiments theviscosity of the gel can range from about 1 to 20 times that of waterand the storage modulus can range from about 200 to 1000 Pascals (over arange of deformations) more preferably form about 200 to 800 Pascals andstill more preferably about 200 to 600 Pascals.

For embodiments of the invention where the viable cells are frozen, theTPA 40 can be modified to accommodate such freezing. For example, thespace within the interior space within TPA for the cell containing gel49 can be increased so as to provide for expansion of the frozen gelwithout damage to the TPA including structural damage such as cracksdisrupting the barrier function of barrier or wall 46′. In eitherapproach, the amount of volumetric empty space of interior of TPA afterfilling with gel 49 can ranch from about 5, to about 90% with specificembodiments of 7.5, 10, 20, 30, 40, 50 and 75%. In a preferredembodiment the amount of volumetric empty space of the interior of theTPA 40 may correspond to the amount of volumetric expansion of waterupon freezing which ranges from about 9 to about 10%.

Also, the TPA including barrier or wall 46′ can be fabricated frommaterials which are resistant to structural damage from freezing such ascracking, crazing etc which may compromise the barrier function of wall46′. Such resistant materials may comprise various low temperaturetolerant biocompatible polymers known in the polymer and biomedicalmaterials arts.

A description will be provided of delivery mechanism 70. Typically, themechanism will comprise a delivery assembly 78 (containing tissuepenetrating articles 40) that is attached to delivery balloon 72 as isshown in the embodiment of FIGS. 6A and 6B. Inflation of the deliveryballoon provides a mechanical force for engaging delivery assembly 72outwards from the capsule and into the intestinal wall IW so as toinsert tissue penetrating articles 40 into the wall. In variousembodiments, the delivery balloon 72 can have an elongated shape withtwo relatively flat faces 72 f connected by an articulatedaccordion-like body 72 b. The flat faces 72 f can be configured to pressagainst the intestinal wall (IW) upon expansion of the balloon 72 so asto insert the tissue penetrating articles (TPAs) 40 into the intestinalwall. TPAs 40 (either by themselves or as part of a delivery assembly 78described below) can be positioned on one or both faces 72 f of balloon70 to allow insertion of viable cells containing TPAs 40 on oppositesides of the intestinal wall. The faces 72 f of balloon 72 may havesufficient surface area to allow for placement of a number of viablecells containing TPAs 40 on each face.

Referring now to FIG. 9, a description will now be provided of assemblyof delivery assembly 78. In a first step 300, one or more tissuepenetrating articles 40 can be detachably coupled to a biodegradableadvancement structure 75 which may correspond to a support platform 75(also known as platform 75). In preferred embodiments, platform 75includes one or more openings 74 for insertion of members 40 as shown instep 300. Openings 74 are sized to allow for insertion and retention ofmembers 40 in platform 75 prior to expansion of balloon 72 whileallowing for their detachment from the platform upon their penetrationinto the intestinal wall. Support platform 75 can then be positionedwithin a carrying structure 76 as shown in step 301. Carrying structure76 may correspond to a well structure 76 having side walls 76 s and abottom wall 76 b which define a cavity or opening 76 c. Platform 75 isdesirably attached to inside surface of bottom wall 76 b using adhesiveor other joining methods known in the art. Well structure 76 cancomprise various polymer materials and may be formed using vacuumforming techniques known in the polymer processing arts. In manyembodiments, opening 76 o can be covered with a protective film 77 asshown in step 302. Protective film 77 has properties selected tofunction as a barrier to protect tissue penetrating articles 40 fromhumidity and oxidation while still allowing tissue penetrating articles40 to penetrate the film as is described below. Film 77 can comprisevarious water and/or oxygen impermeable polymers which are desirablyconfigured to be biodegradable in the small intestine and/or to passinertly through the digestive tract. It may also have a multi-plyconstruction with particular layers selected for impermeability to agiven substance, e.g., oxygen, water vapor etc. In use, embodimentsemploying protective film 77 serve to increase the shelf life oftherapeutic agent 101 in tissue penetrating articles 40, and in turn,the shelf life of device 10. Collectively, support platform 75 attachedtissue penetrating articles 40, well structure 76, and film 77 cancomprise a delivery assembly 78. Delivery assemblies 78 having one ormore viable cells or therapeutic agents 101 contained within tissuepenetrating article 40 or other viable cells delivery means can bepre-manufactured, stored and subsequently used for the manufacture ofdevice 10 at a later date. The shelf life of assembly 78 can be furtherenhanced by filling cavity 76 c of the sealed assembly 78 with an inertgas such as nitrogen.

Referring back to FIGS. 6A and 6B, assemblies 78 can be positioned onone or both faces 72 f of balloon 72. In preferred embodiments,assemblies 78 are positioned on both faces 72 f (as shown in FIG. 6A) soas to provide a substantially equal distribution of force to oppositesides of the intestinal wall IW upon expansion of balloon 72. Theassemblies 78 may be attached to faces 72 f using adhesives or otherjoining methods known in the polymer arts. Upon expansion of balloon 72,TPAs 40 penetrate through film 77, enter the intestinal wall IW and areretained there by retaining elements 43 and/or other retaining featuresof tissue penetrating (e.g., an inverse tapered shaft 44 t) such thatthey detach from platform 75 upon deflation of balloon 72.

In various embodiments, one or more of balloons 30, 60 and 72 can bepacked inside capsule 20 in a folded, furled or other desiredconfiguration to conserve space within the interior volume 24 v of thecapsule. Folding can be done using preformed creases or other foldingfeature or method known in the medical balloon arts. In particularembodiments, balloon 30, 60 and 72 can be folded in selectedorientations to achieve one or more of the following: i) conserve space,ii) produce a desired orientation of a particular inflated balloon; andiii) facilitate a desired sequence of balloon inflations. Theembodiments shown in FIGS. 5A-5F illustrate an embodiment of a method offolding and various folding arrangements. However, it should beappreciated that this folding arrangement and the resulting balloonorientations are exemplary and others may also be used. In this andrelated embodiments, folding can be done manually, by automated machineor a combination of both. Also in many embodiments, folding can befacilitated by using a single multi balloon assembly 7 (herein assembly7) comprising balloons 30, 60, 70; valve chamber 58 and assortedconnecting tubing 62 as is shown in the embodiments of FIGS. 3A and 3B.FIG. 3A shows an embodiment of assembly 7 having a single domeconstruction for balloon 30, while FIG. 3B shows the embodiment ofassembly 7 having dual balloon/dome configuration for balloon 30.Assembly 7 can be fabricated using a thin polymer film which isvacuum-formed into the desired shape using various vacuum forming andother related methods known in the polymer processing arts. Suitablepolymer films include polyethylene films having a thickness in the rangeof about 0.003 to about 0.010″, with a specific embodiment of 0.005″. Inpreferred embodiments, the assembly is fabricated to have a unitaryconstruction so as to eliminate the need for joining one or morecomponents of the assembly (e.g., balloons 30, 60, etc.). However, it isalso contemplated for assembly 7 to be fabricated from multiple portions(e.g., halves), or components (e.g., balloons) which are then joinedusing various joining methods known in the polymer/medical device arts.

Referring now to FIGS. 5A-5F, 6A-B and 7A-7B, in a first folding step210, balloon 60 is folded over onto valve fitting 58 with balloon 72being flipped over to the opposite side of valve fitting 58 in theprocess (see FIG. 5A). Then in step 211, balloon 72 is folded at a rightangle to the folded combination of balloon 60 and valve 58 (see FIG.5B). Then, in step 212 for dual dome embodiments of balloon 30, the twohalves 30′ and 30″ of balloon 30 are folded onto each other, leavingvalve 50 exposed (see FIG. 5C, for single dome embodiments of balloon30, is folded over onto itself see FIG. 5E). A final folding step 213can be done whereby folded balloon 30 is folded over 180° to theopposite side of valve fitting 58 and balloon 60 to yield a final foldedassembly 8 for dual dome configurations shown in the FIG. 5E and a finalfolded assembly 8′ for single dome configurations shown in FIGS. 5E and5F. One or more delivery assemblies 78 are then be attached to assembly8 in step 214 (typically two the faces 72 f of balloon 72) to yield afinal assembly 9 (shown in the embodiments of FIGS. 6A and 6B) which isthen inserted into capsule 20. After an insertion step 215, the finalassembled version of device 10 with inserted assembly 9 is shown FIGS.7A and 7B.

Referring now to FIGS. 10A-10I, a description will be provided of amethod of using device 10 to deliver viable therapeutic cells 101 to asite in the GI tract such as the wall of the small or large intestine.It should be appreciated that the steps and there order is exemplary andother steps and orders also contemplated. After device 10 enters thesmall intestine SI, the cap coating 20 c′ is degraded by the basic pH inthe upper small intestine causing degradation of cap 20 p′ as shown instep 400 in FIG. 10B. Valve 50 is then exposed to fluids in the smallintestine causing the valve to begin degrade as is shown in step 401 inFIG. 10C. Then, in step 402, balloon 30 expands (due to generation ofgas 69) as shown in FIG. 10D. Then, in step 403, section 60′ of balloon60 begins to expand to start to push assembly 78 out of the capsule bodyas shown in FIG. 10E. Then, in step 404, sections 60′ and 60″ of balloon60 become fully inflated to completely push assembly 78 out of thecapsule body extending the capsule length 201 so as to serve to aligncapsule lateral axis 20AL with the lateral axis of the small intestineLAI as shown in FIG. 10F. During this time, valve 55 is beginning tofail from the increased pressure in balloon 60 (due to the fact that theballoon has fully inflated and there is no other place for gas 69 togo). Then, in step 405, valve 55 has completely opened, inflatingballoon 72 which then pushes the now completely exposed assembly 78(having been pushed completely out of body 20 p″) radially outward intothe intestinal wall IW as shown in FIG. 10G. Then, in step 406, balloon72 continues to expand to now advance tissue penetrating articles intothe intestinal wall IW as shown in FIG. 10H. Then, in step 407, balloon72, (along with balloons 60 and 30) has deflated pulling back andleaving tissue penetrating articles retained in the intestinal wall IW.Also, the body portion 20 p″ of the capsule has completely degraded (dueto degradation of coating 20 c″) along with other biodegradable portionsof device 10. Any portion not degraded is carried distally through thesmall intestine by peristaltic contraction from digestion and isultimately excreted.

Referring back to FIG. 1B, as an alternative or supplement to the use ofpH sensitive degradable coatings and valves for inflation of one or moreof balloons 30, 60, and 72 (and deployment of cell preparation 100), invarious embodiments the balloons can be expanded responsive to a sensor97, such as a pH sensor 98 or other chemical sensor which detects thepresence of the capsule in the small intestine. Sensor 97 can then senda signal to a controllable embodiment of isolation valve 50 or to anelectronic controller 29 c coupled to a controllable isolation valve 50to open and thus expand balloon 30 as is described herein. Embodimentsof a pH sensor 98 can comprise an electrode-based sensor or it can be amechanically-based sensor such as a polymer which shrinks or expandsupon exposure to a selected pH or other chemical conditions in the smallintestine. In related embodiments, an expandable/contractible pH sensor98 can also comprise the isolation valve 50 itself, by configuring thesensor to expand or contract about connector 63 and/or 36 so as to opena channel between balloons 30 and 60 and/or compartments 34 and 35.

According to another embodiment for detecting when device 10 is in thesmall intestine (or other location in the GI tract), sensor 97 cancomprise pressure/force sensor such as strain gauge for detecting thenumber of peristaltic contractions that capsule 20 is being subject towithin a particular location in the intestinal tract (in suchembodiments capsule 20 is desirably sized to be gripped by the smallintestine during a peristaltic contraction). Different locations withinthe GI tract have different number of peristaltic contractions. Forexample, the small intestine has between 12 to 9 contractions per minutewith the frequency decreasing down the length of the intestine. Thus,according to one or more embodiments, detection of the number ofperistaltic contractions can be used to not only determine if capsule 20is in the small intestine, but the relative location within theintestine as well. In use, these and related embodiments allow forrelease of viable therapeutic cells 101 and or cell preparation 100 at aparticular location in the small intestine.

Still referring to FIG. 1B, as an alternative or supplement to internalactivation of the delivery by device 10 (e.g., using a pH sensitivecoatings and/or sensor), in some embodiments, the user may externallysend a signal to expand one or more of balloon 30, 60 and 72 to deliverviable therapeutic cells 101 to the intestinal wall. The signal may besent by means of RF, magnetic or other wireless signaling means known inthe art. In various embodiments, external activation can be achieved byuse of a controllable isolation valve 50 for example, an RF controlledminiature solenoid valve or other electro-mechanical control valve (notshown). In other embodiments, a controllable isolation valve 50 maycorrespond to a miniature magnetically valve such as a magneticallycontrolled miniature reed switch (not shown). Such electromechanical ormagnetic-based valves can be fabricated using mems and other micromanufacturing methods. In these and related embodiments, the user canuse a handheld communication device 13 (e.g., a hand held RF device suchas a cell phone) as is shown in the embodiment of FIG. 1B, to send areceive signals 17 from device 10. In such embodiments, swallowabledevice may include a transmitter 28 such as an RF transceiver chip orother like communication device/circuitry. Handheld device 13 may notonly includes signaling means, but also means for informing the userwhen device 10 is in the small intestine or other location in the GItract. The later embodiment can be implemented through the use of logicresources 29 (e.g., a processor 29) coupled to transmitter 28 to signalto detect and singe to the user when the device is in the smallintestine or other location (e.g., by signaling an input from thesensor). Logic resources 29 may include a controller 29 c (either inhardware or software) to control one or more aspects of the process. Thesame handheld device can also be configured to alert the user whenballoon 30 as well as balloons 52 and 60 have been expanded and theselected cell preparation 100 and viable therapeutic cells 101 have beendelivered (e.g., using processor 29 and transmitter 28). In this way,the user is provided confirmation that cell preparation 100 has beendelivered. This allows the user to take other appropriate therapeuticagents as well as make other related decisions (e.g., for diabetics toeat a meal or not and what foods should be eaten). The handheld devicecan also be configured to send a signal to swallowable device 10 toover-ride isolation valve 50 and so prevent, delay or accelerate thedelivery of viable therapeutic cells 101. In use, such embodiments allowthe user to intervene to prevent, delay or accelerate the delivery ofviable therapeutic cells, based upon other symptoms and/or patientactions (e.g., eating a meal, deciding to go to sleep, exercise etc.).The user may also externally expand balloon 30 or expandable member 30at a selected time period after swallowing the capsule. The time periodcan be correlated to a typical transit time or range of transit timesfor food moving through the user's GI tract to a particular location inthe tract such as the small intestine.

Referring now to FIGS. 11A-11B and 16, in various embodiments, thecapsule 20 can include seams 22 comprising biodegradable material whichcontrollably degrade to produce capsule pieces 23 of a selectable sizeand shape to facilitate passage through the GI tract as is shown in theembodiment of FIGS. 11A and 11B. Seams 22 can also include pores orother openings 22 p for ingress of fluids into the seam to acceleratebiodegradation as is shown in the embodiment of FIG. 16. Other means foraccelerating biodegradation of seams 22 can include pre-stressing theseam and/or incorporating degradation nucleation sites in the seams.

Referring now to FIGS. 12A-12C, in other embodiments of a swallowableviable cell delivery device 10, the device 10 may include one or morepiston cylinder assemblies (PCA) 250 for delivering one or more needlesor other tissue penetrating articles (TPA) 40 into the intestinal wall.As such, in these and related embodiments, the piston cylinder assembly(PCA) comprises the delivery mechanism 70. Typically, the pistoncylinder assembly (PCA) 250 will be positioned substantially inside aballoon such as balloon 260. However, they may be positioned partiallyor even completely outside of balloon 260 or other balloon describedherein. In some embodiments the balloon 260 comprises multiple portions.As shown in FIG. 12A, the balloon 260 comprises two portions, the firstportion comprises a first compartment 265 and the second portioncomprises a second compartment 266 separated by a release valve assembly290. One portion contains a solid reactant 810 such as potassiumbicarbonate and the other portions contains a liquid reactant 811 suchas citric acid which reacts with the solid reactant to produce a gas 299such as CO₂. The valve assembly 290 comprises an O-ring 270 positionedover a dissolvable pinch valve 292 which pinches down and maintains aseal between the two portions 265 and 266 of the balloon 260. Thedissolvable valve is fabricated from maltose or other material whichdissolves upon contact with fluid in the small intestine. When thathappens, fluid from one portion of the balloon mixes with the reactantin the other to generate the gas 299 to inflate the balloon 260.

Typically, the PCA 250 is positioned in the portion/compartment of theballoon 260 containing the solid reactants (second compartment 266) andis dimensioned accordingly. In one more embodiments, the balloon canhave a vertical height between about 12 to 16 mm, with a preferredembodiment of 14 mm, while the inner diameter of the balloon 260 can bein the range of 18 to 22 mm with a preferred embodiment of 20 mm. Otherdimensions are also contemplated. In various embodiments, all or portionof the PCA 250 is fabricated from materials which can be dissolvablematerials such maltose, or methyl cellulose. It can also be fabricatedfrom ABS and other polymers which are inert within the GI tract. Inspecific embodiments, the outer top portion of the piston can be made ofsilicone which is mounted on an inner structure, such as a pedestalstructure which can be made of ABS.

As shown in FIG. 12A, when uninflated, the PCA 250 is positionedsideways (horizontally) within the balloon 260 (with respect to thelengthwise axis of the balloon), but when the balloon 260 is inflatedthe PCA 250 re-orients itself to a vertical position as shown in FIG.12B. This reorientation can be achieved by virtue of conformation/shapechanges once the balloon 260 is inflated as well as by means of anadhesive or other joint 269 attached the PCA 250 to the balloon wall 261which can be configured to exert a force on the PCA 250 to bias it intoa vertical orientation (ie., the joint is made when the PCA 250 is in avertical position and then the PCA is put into a horizontal position).The joint 269 may comprise various elastic materials known in the artincluding silicone. The PCA comprises a piston 252 and piston rod 253which are positioned inside a cylinder 251 (aka piston cylinder). Theneedle or TPA 40 sits above the piston rod 253 within a needle lumen 230which is continuous with the piston cylinder. The needle lumen can alsoinclude a covering 231 (herein needle lumen covering) which can comprisea foil or polymer film. The ratio in diameter between the piston andpiston rod can be selected to result in desired pressure concentrationeffect (e.g., 2:1, 3:1, etc) from the decrease in surface area. AnO-ring 271 is positioned between the piston 252 and the piston cylinder251 to maintain a seal between the piston 252 and the wall of the pistoncylinder 251. Also, a pressure sensitive release 235 is positionedinside the cylinder 251 to keep the piston 252 in place until desiredpressure (also referred to as a pressure threshold) has built up (e.g.,5 to psi 20 psi, more preferably 8 to 10 psi) inside balloon 260. Therelease 235 may correspond to a tab, latch or an O-ring. In use, thisrelease serves to assure that there is sufficient pressure within theballoon to drive the needle 40 a desired depth into the wall of thesmall intestine (IW).

When the valve separating the two portions (265 and 266) of the balloon260 dissolves and the balloon begins to inflate, the PCA 250 re-orientsitself from a horizontal to vertical orientation as described above.Then, when the pressure in the balloon 260 exceeds the release pressureof the release tab, the piston rod advances against the needle (or otherTPA) to force the needle 40 out of the needle lumen 230 and into thewall of the small intestine. Once the needle passes through the needlelumen into the intestinal wall, the balloon 260 then deflates via thenow open needle lumen. After needle deployment, the PCA 250 eitherdissolves or passes harmlessly through the GI tract.

In one or more embodiments, the delivery mechanism 70 can comprise anarray 350 of the PCAs (multiple needle PCA) that can be configured forthe delivery of multiple needles 40 (or other TPA) as shown in FIG. 12C.In these and related embodiments, the PCAs can include a commoninflation manifold 357 coupled to multiple needle lumens 330 via centrallumen 358 at one end and to the balloon 359 at the other. Variousembodiments of a multiple needle PCA 350 can be configured to deliverfrom 2 to 6 needles or more. Each needle may contain the same ordifferent viable cells or other therapeutic agent.

As described above, deflation of the delivery balloon 260 occurs throughthe needle lumen once the needle has been delivered into tissue with noadditional means for balloon deflation needed.

Referring now to FIG. 12D, in alternative embodiments, the deliveryballoon 260 may also include a separate deflation valve assembly 280which serves as backup or secondary means for deflation in addition tothe needle lumen 230. As shown in FIG. 12D, the deflation valve assemblycomprises an O-ring 272 positioned over a dissolvable pinch valve 281which pinches down an open end of the delivery balloon 260. The valveincludes a dissolvable body portion made of maltose or other similarmaterial as the release valve and an outer coating such as methylcellulose. The outer coating 283 is configured to take a substantiallylonger time to dissolve than the dissolvable valve in the release valveassembly such that the deflation valve is not actuated for periods of 10minutes or longer (preferably 20) after the release valve is actuated.This is to assure that deflation valve is not accuated until well afterthe needle has been advanced into the intestinal wall.

Referring now to FIG. 13A-13B, in one or more embodiments of theswallowable device, the delivery balloon 460 can include an assemblyconfigured to both control pressure at which the needle is advanced outof the balloon and into the intestinal wall as well as assure thatballoon deflates by means of puncture. The assembly can include a lowerportion 463 to which one or more TPAs (herein also referred to as viablecell needles) 40 are attached and an upper portion 464 to which one ormore puncture needles (puncture members) 450 are attached. The upperportion may include an aperture 430 or opening for the TPA to beadvanced out of the assembly and into the intestinal wall. Upper portion464 and lower portion 463 may be joined by sidewalls 465. Sidewalls 465may be collapsible to permit portions 464 and 463 to come together.Sidewalls 465 may have enough rigidity to keep the upper portion 464 andlower portion 463 apart while balloon 460 is not inflating. Sidewalls465, collapse however under the balloon pressure. The sidewalls may beweakly bonded to the balloon 460 with weak adhesive 470 such that thesidwalls conform to the balloon until the balloon 460 inflates. Uponinflation of balloon 460, the sidewalls 465 separate from the balloon460. Lower portion 463 may also be bonded to the balloon, but withstronger adhesive adhesive 469. The entire assembly is positionedbetween the balloon and the intestinal wall IW as shown in FIG. 13A.

Upon inflation of the delivery balloon 460, the puncture needles 450 areconfigured to penetrate and puncture the lower portion 463 of thedelivery assembly and the delivery balloon 460 in order to rupture thedelivery balloon. Preferably, the TPA needles 40 have a length 401sufficiently longer than the length of the puncture needles 4501 suchthat the TPA 40 is already on its way out of the assembly and even intothe intestinal wall before the puncture needles 450 make contact withthe lower portion 463 and the balloon 460. According to one or moreembodiments, the TPA needle is between 25 to 300% longer than punctureneedles with specific embodiments, of 50, 75, 100, 150, 200 and 250%.

According to one or more embodiments, the lower portion 463 isfabricated from a material which does not allow the puncture needle topenetrate until a desired pressure is reached (e.g., 4 to 20 psi, morepreferably 8 to 12 psi). This in turn keeps the TPA needle from beingcompletely advanced out into the intestinal wall until the desiredpressure is reached. Once the puncture needles 450 penetrate the lowerportion 463, they allow the TPA needle 40 to be completely advanced out,while simultaneously puncturing the inflated balloon 460 to ensuredeflation. These and related embodiments provide the benefit of bothcontrolling the pressure at which the TPA needle 40 is advanced,assuring that the balloon is deflated.

FIG. 13B shows the Balloon Inflation Pressure (BIP) 702 and the punctureneedle pressure (PNP) 701, the pressure used to advance the punctureneedles to penetrate balloon 460 and lower portion 463, as timeprogresses. The PNP rises and peaks as the puncture needles begin topenetrate the lower portion 463. Once penetration of the lower portion463 and balloon 460 is complete PNP drops to zero. After the TPA needle40 has been fully inserted into the intestinal wall the gas inside theballoon 460 is able to escape out of aperture 430 and BIP drops to zeroas the balloon 460 deflates. In various embodiments, the entire assemblycan be fabricated from various biodegradable or inert polymers know inthe art. The pressure at which the lower portion 463 is penetrated canbe controlled by one or more of the thickness and materials for thelower portion 463. In various embodiments, the lower portion 463 can befabricated from a polymer film including various inert (acrylonitrilebutadiene styrene (ABS)) and/or biodegradable polymer films known in theart (e.g., methylcellulose).

According to one or more embodiments, the TPA needle or other tissuepenetrating article 40 can be fabricated from methyl cellulose polymers.Such methyl cellulose polymers can include hydroxy methyl cellulose,carboxy methyl cellulose and various polymer thereof. The advantages ofthe use of such methyl cellulose polymers for fabrication of the TPAneedle (or other tissue penetrating article) compared to maltose-basedTPA needles include little or no sensitivity to humidity during storage,reduced wall thickness, smaller needle size with the same viable cellspayload, and ability to process the needle after fabrication includingprocessing such as grinding, sharpening, sanding and other relatedprocesses. In one or more embodiments, a methyl cellulose-based TPAneedle may have a wall thickness in the range of 0.05 to 0.15 mm with aspecific embodiment of 0.1 mm. Also in one more embodiments, the methylcelluolse-based TPA needle may carry between 25-150% more viable cellsversus a same sized maltose-based TPA. In a specific embodiment of a TPAneedle having an outer diameter of 1.5 mm, the methyl cellulose needlecan carry 100% more viable cells versus a maltose-based needle.

Referring now to FIGS. 15A-15B and 16, in many embodiments seams 22 canalso be configured and arranged so as to allow capsule 20 to be brokeninto smaller pieces by the inflation of balloon 30 or other expandablemember 30. In particular embodiments, seams 22 can be oriented withrespect to capsule radial perimeter 21, including having a radialpattern 22 rp so as to have the capsule break into halves or otherfractional pieces along its perimeter. Seams 22 may also belongitudinally-oriented with respect to capsule lateral access 201 a tohave the capsule break up into lengthwise pieces.

As an alternative or additional approach for breaking up capsule 20 byballoon inflation (or expansion of other expandable member 30), capsule20 can be fabricated from two or more separate joinable pieces 23 j(e.g., radial halves) that are joined at a joint 22 j formed by seams 22(which function as an adhesive joint) as shown in the embodiment of FIG.16. Alternatively, joinable pieces 23 j may be merely joined by amechanical fit such as a snap or press fit.

Suitable materials for seams 22 can include one or more biodegradablematerials described herein such as PLGA, glycolic acid etc. Seams 22 canbe attached to capsule 20 using various joining methods known in thepolymer arts such as molding, hot melt junctions, etc. Additionally forembodiments of capsule 20 which are also fabricated from biodegradablematerials, faster biodegradation of seam 22 can be achieved by one ormore of the following: i) fabricating the seam from a fasterbiodegrading material, ii) pre-stressing the seam, or iii) perforatingthe seam. The concept of using biodegradable seams 22 to producecontrolled degradation of a swallowable device in the GI tract can alsobe applied to other swallowable devices such as swallowable cameras (orother swallowable imaging device) to facilitate passage through the GItract and reduce the likelihood of such a device becoming stuck in theGI tract. Accordingly, embodiments of biodegradable seam 22 can beadapted for swallowable imaging and other swallowable devices.

In still other embodiments, seam 22 can be constructed of materialsand/or have a structure which is readily degraded by absorption ofultrasound energy, e.g. high frequency ultrasound (HIFU), allowing thecapsule to be degraded into smaller pieces using externally orendoscopically (or other minimally invasive method) administeredultrasound.

Another aspect of the invention provides methods for the delivery ofviable cells 101 and other therapeutic agents (into the walls of the GItract using one or more embodiments of swallowable viable cell deliverydevice 10. An exemplary embodiment of such a method will now bedescribed. The described embodiment of viable cells delivery occurs inthe small intestine SI. However, it should be appreciated that this isexemplary and that embodiments of the invention can be used fordelivering viable cells in a number of locations in the GI tractincluding the stomach and the large intestine. For ease of discussion,the swallowable viable cells delivery device 10 will sometimes bereferred to herein as a capsule. As described above, in variousembodiments device 10 may be packaged as a kit 14 within sealedpackaging 12 that includes device 10 and a set of instructions for use15. If the patient is using a handheld device 13, the patient may beinstructed to enter data into device 13 either manually or via a barcode 18 (or other identifying indicia 18) located on the instructions 15or packaging 12. If a bar code is used, the patient would scan the barcode using a bar code reader 19 on device 13. After opening packaging12, reading the instructions 15 and entering any required data, thepatient swallows an embodiment of the swallowable viable cells deliverydevice 10. Depending upon the viable cells, the patient may take thedevice 10 in conjunction with a meal (before, during or after) or aphysiological measurement such as a blood glucose measurement. Capsule20 is sized to pass through the GI tract and travels through thepatient's stomach S and into the small intestine SI through peristalticaction as is embodied in device 10 shown in the embodiment of FIG. 1E.Once the capsule 10 is in the small intestine, coatings 20 c′ and 20 c″are degraded by the basic pH in the small intestine (or other chemicalor physical condition unique to the small intestine) causing expansionof balloon 30, 60 and 72 or deliver viable therapeutic cells 101 intothe wall of the small intestine SI according to one or more embodimentsof the invention.

After viable cell delivery, device 10 then passes through the intestinaltract including the large intestine LI and is ultimately excreted. Forembodiments having a tearable capsule, the capsule may immediately bebroken into smaller pieces by inflation of balloon 30. For embodimentsof the capsule 20 having biodegradable seams 22 or other biodegradableportions, the capsule is degraded in the intestinal tract into smallerpieces, to facilitate passage through and excretion from the intestinaltract. In particular embodiments having biodegradable tissue penetratingneedles/members 40, should the needle get stuck in the intestinal wall,the needle biodegrades releasing the capsule 20 from the wall.

For embodiments of device 10 including a sensor 97, expansion of balloon30 or other expandable member 30 can be effectuated by the sensorsending a signal to a controllable embodiment of isolation valve 50and/or a processor 29/controller 29 c coupled to the isolation valve 50.For embodiments of device 10 including external actuation capability,the user may externally expand balloon 30 (as well as balloons 52 and60) at a selected time period after swallowing the capsule. The timeperiod can be correlated to a typical transit time (e.g., 30 minutes) orrange of transit times (e.g., 10 minutes to 2 hrs.) for food movingthrough the user's GI tract to a particular location in the tract suchas the small intestine.

The foregoing description of various embodiments of the invention hasbeen presented for purposes of illustration and description. It is notintended to limit the invention to the precise forms disclosed. Manymodifications, variations and refinements will be apparent topractitioners skilled in the art. For example, embodiments of the devicecan be sized and otherwise adapted for various pediatric and neonatalapplications as well as various veterinary applications. Also thoseskilled in the art will recognize, or be able to ascertain using no morethan routine experimentation, numerous equivalents to the specificdevices and methods described herein. Such equivalents are considered tobe within the scope of the present invention and are covered by theappended claims below.

Elements, characteristics, or acts from one embodiment can be readilyrecombined or substituted with one or more elements, characteristics oracts from other embodiments to form numerous additional embodimentswithin the scope of the invention. Moreover, elements that are shown ordescribed as being combined with other elements, can, in variousembodiments, exist as standalone elements. Hence, the scope of thepresent invention is not limited to the specifics of the describedembodiments, but is instead limited solely by the appended claims.

What is claimed is:
 1. A method for orally delivering viable cells tointestinal tissue of a patient, the method comprising: swallowing a drugdelivery device containing a tissue penetrating article which contains amass of viable cells, wherein the article passes through thegastrointestinal tract with the article intact and the cells remainingviable; releasing the article from the drug delivery device in responseto a condition in the intestine; and propelling the article to penetrateinto the intestinal tissue and release the cells or substances producedby the cells into the intestinal tissue.
 2. The method of claim 1,wherein the intestinal tissue is intestinal wall tissue, small intestinewall tissue or peritoneal wall tissue.
 3. The method of claim 1, whereinthe delivered cells reseed a portion of the mucosa or lining of thesmall intestine, large intestine, or stomach.
 4. The method of claim 1,wherein the condition is a pH or a pH in the small intestine.
 5. Themethod of claim 2, wherein the pH in the small intestine is above about7.1.
 6. The method of claim 1, wherein propelling the article comprisesapplying a propulsive force by means of the expansion of an expandablemember.
 7. The method of claim 6, wherein the expandable member isexpanded by a chemical reaction triggered in response to a pH in thesmall intestine or other location in the gastrointestinal tract.
 8. Themethod of claim 1, wherein the cells are in a suspended reanimatablestate prior to being ingested by the patient.
 9. The method of claim 8,wherein the cells are reanimated after ingestion of the drug deliverydevice.
 10. The method of claim 9, wherein the cells are reanimated bythe patient's body temperature.
 11. The method of claim 9, wherein thecells are reanimated by conditions in the intestinal tissue including atleast one of temperature, blood supply or oxygen supply.
 12. The methodof claim 8, wherein the cells are frozen prior to being swallowed by thepatient.
 13. The method of claim 12, wherein the cells at leastpartially thaw as they pass through the gastro-intestinal tract.
 14. Themethod of claim 1, wherein the cells are protected from conditions ofthe gastrointestinal tract by a barrier provided by the article.
 15. Themethod of claim 14, wherein the barrier remains intact while the articlepasses through the gastrointestinal tract and biodegrades within theintestinal tissue.
 16. The method of claim 15, wherein the barrier isconfigured to biodegrade over a time period of at least about 12 hours.17. The method of claim 16, wherein the time period is in a range fromabout 1 to 5 days.
 18. The method of claim 15, wherein the barriercomprises a biodegradable polymer.
 19. The method of claim 18, whereinthe biodegradable polymer is selected from a group consisting of polylactic acid (PLA), poly lactic-co-glycolic acid (PLGA) and maltose. 20.The method of claim 1, wherein the barrier comprises a wall havingfenestrations.
 21. The method of claim 20, wherein the fenestrations areconfigured to allow the passage of fluids and molecules but contain thecells and gel, at least a portion of the barrier including fenestrationshaving a slower rate of biodegradation relative to the rest of thebarrier.
 22. The method of claim 21, wherein the fenestrations have awidth in the range from about 0.5 μm to 5 μm or an area in the rangefrom 0.8 μm² to 80 μm².
 23. The method of claim 21, wherein at least aportion of the cells remain in the article and produce a therapeuticcompound which diffuses out of the fenestrations.
 24. The method ofclaim 20, where the fenestrations are configured as echogenic markers toallow for location of the barrier in the body using ultrasonic imaging,the method further comprising: ultrasonic imaging the body of thepatient to locate the barrier using the fenestrations.
 25. The method ofclaim 24, where the fenestrations are configured to provide anindication of a degree of biodegradation of the barrier, the methodfurther comprising: ultrasonic imaging the body of the patient toascertain a degree of biodegradation of the barrier.
 26. The method ofclaim 1, wherein the cells are present in a viability-sustaining gel.27. The method of claim 26, wherein the viability-sustaining gelcomprises at least one of an alginate, a protein, a glycosaminoglycan,and polysaccharide.
 28. The method of claim 26, wherein theviability-sustaining gel is at least partially saturated with oxygen topreserve the viability of the cells.
 29. The method of claim 26, whereinthe viability-sustaining gel is at least partially saturated withnitrogen or other inert gas to preserve the viability of the cells. 30.The method of claim 1, wherein the viable cells are therapeutic cells,entero-endocrine cells, gastric enteroendocrine cells, or intestinalenteroendocrine cells.
 31. The method of claim 30, wherein the viablecells are selected from a group consisting of pancreatic B-cells,L-cells, K-cells, G-cells, I cells, immune cells, stem cells,mesenchymal stem cells, and hematopoietic stem cells.
 32. The method ofclaim 1, wherein once delivered into intestinal tissue, the cellsproduce a therapeutic compound released within the body.
 33. The methodof claim 32, wherein the therapeutic compound comprises a glucoseregulating compound, insulin, an incretin, or Gastrin.
 34. The method ofclaim 32, wherein at least a portion of the cells remain in the articlewhile producing the therapeutic compound.
 35. A method for orallydelivering viable cells to intestinal tissue of a patient, the methodcomprising: swallowing a drug delivery device containing a tissuepenetrating article which contains a mass of viable cells in a suspendedreanimatable state, wherein the article passes through thegastrointestinal tract with the article intact and the cells remainingviable; releasing the article from the drug delivery device in responseto a condition in the intestine; and propelling the article to penetrateinto the intestinal tissue to release the cells or substances producedby the cells into the intestinal tissue and wherein the cells arereanimated by a condition in the patient's body.